Environmental enrichment shapes striatal spike-timing-dependent plasticity in vivo

Morera-Herreras, Teresa; Gioanni, Yves; Perez, Sylvie; Vignoud, Gaetan; Venance, Laurent

doi:10.1038/s41598-019-55842-z

Environmental enrichment shapes striatal spike-timing-dependent plasticity in vivo

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Published: 19 December 2019

Volume 9, article number 19451, (2019)
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Environmental enrichment shapes striatal spike-timing-dependent plasticity in vivo

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Teresa Morera-Herreras^1,2,3^na1,
Yves Gioanni¹^na1,
Sylvie Perez¹,
Gaetan Vignoud¹ &
…
Laurent Venance ORCID: orcid.org/0000-0003-0738-1662¹

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Abstract

Behavioural experience, such as environmental enrichment (EE), induces long-term effects on learning and memory. Learning can be assessed with the Hebbian paradigm, such as spike-timing-dependent plasticity (STDP), which relies on the timing of neuronal activity on either side of the synapse. Although EE is known to control neuronal excitability and consequently spike timing, whether EE shapes STDP remains unknown. Here, using in vivo long-duration intracellular recordings at the corticostriatal synapses we show that EE promotes asymmetric anti-Hebbian STDP, i.e. spike-timing-dependent-potentiation (tLTP) for post-pre pairings and spike-timing-dependent-depression (tLTD) for pre-post pairings, whereas animals grown in standard housing show mainly tLTD and a high failure rate of plasticity. Indeed, in adult rats grown in standard conditions, we observed unidirectional plasticity (mainly symmetric anti-Hebbian tLTD) within a large temporal window (~200 ms). However, rats grown for two months in EE displayed a bidirectional STDP (tLTP and tLTD depending on spike timing) in a more restricted temporal window (~100 ms) with low failure rate of plasticity. We also found that the effects of EE on STDP characteristics are influenced by the anaesthesia status: the deeper the anaesthesia, the higher the absence of plasticity. These findings establish a central role for EE and the anaesthetic regime in shaping in vivo, a synaptic Hebbian learning rule such as STDP.

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Introduction

Behavioural experience, such as environmental enrichment (EE), has profound long-term effects on learning and memory performance^1,2,3,4,5. EE, which combines complex inanimate and social interactions^6,7, provides sensory, motor and cognitive stimulation that are normally lacking in standard rodent housing. Rearing animals in EE aims at mimicking the circumstances of a stimulating and interesting living environment that is conductive to cognitive functions. Cognitive functions are mainly characterised by synaptic plasticity that scales in both directions of the synaptic weight, widely observed with long-term potentiation (LTP) and long-term depression (LTD)^8,9. Synaptic strength between neurons can be modified by their relative activity on either side of the synapse as postulated many decades ago by Donald Hebb¹⁰. More precisely, the firing of the first neuron would influence long-term the firing of the second one as a means of storing a memory trace. The corresponding cellular paradigm consists the spike-timing dependent plasticity (STDP), a synaptic Hebbian learning rule in which occurrence of timing-dependent-LTP (tLTP) or -LTD (tLTD) relies on the precise (milliseconds) relative timing of pre- and postsynaptic action potentials¹¹. STDP has emerged as a candidate mechanism for experience-dependent changes in the neural circuit, including map plasticity¹¹. The temporal rules of STDP are determined by the spatial location of dendritic inputs^12,13,14, factors affecting dendritic voltage-gated channel properties¹⁵, gamma-aminobutyric acid (GABA)^16,17,18, or by neuromodulators^19,20. In brief, events modulating the electrotonic properties of the dendritic tree and thus of the back-propagating action potential, are expected to shape STDP. Although EE is known to control neuronal excitability through dendritic morphology²¹, channel, and receptor expression or modification of the balance between excitation and inhibition¹, whether EE controls STDP remains unknown. To date, the vast majority of studies have characterised in detail the molecular, structural, and synaptic changes in animals exposed to EE by using ex vivo brain slices and assessed changes in synaptic plasticity using frequency-based protocols (high- or low stimulation frequency protocols). The effect of EE on synaptic strength in ex vivo preparations is controversial, describing either an increase in synaptic strength or an absence of an effect²². These discrepancies could be due to slice preparation methodology, which could alter or mask the in vivo EE effect in adult animals^22,23. Thus, it is necessary to examine Hebbian synaptic plasticity in vivo at the single-cell level in adult rodents raised in EE.

EE is known to improve learning of procedural tasks such as the accelerating rotarod treadmill²⁴. Striatal synaptic plasticity provides a fundamental mechanism for basal ganglia function for action control and procedural learning^{25,26,27,28,29,30}. Here, we aimed at examining the effects of EE on STDP temporal rules in the dorsolateral striatum in vivo. For this purpose, we performed in vivo long-duration intracellular recordings (sharp pipette electrode) of striatal projecting neurons (the medium-sized spiny neurons, MSNs) to investigate STDP in rats grown in standard environment (SE) or EE with various anaesthetic regimes (deep vs light levels of anaesthesia). We found that EE (together with the anaesthetic level) has a crucial impact on STDP. Rats reared in SE under deep anaesthesia, displayed mainly tLTD in a wide temporal window (Δt_STDP) (−100 < Δt_STDP < +100 ms) for post-pre and pre-post cortico-striatal pairings, together with a high rate of failure of plasticity expression. In contrast, rats reared in EE for two months exhibited bidirectional STDP with tLTP occurring after post-pre pairings with −100 < Δt_STDP < −50 ms, whereas tLTD occurred in a large temporal window, i.e. −50 < Δt_STDP < +100 ms. Under light anaesthesia, we observed bidirectional STDP in rats raised either in SE or EE. Interestingly, rats grown in EE displayed bidirectional STDP in a restricted temporal window, comparable to STDP observed in ex vivo studies, i.e. −40 < Δt_STDP < +40 ms, also showing a high rate of plasticity expression. In conclusion, EE promotes bidirectional STDP in a restricted temporal window with high rate of plasticity expression.

Materials and Methods

Animals

Experiments were conducted in adult (P_65-90) male Sprague-Dawley rats (Charles River, L’Arbresle, France). All experimental protocols and methods (maintenance, surgery and all experiments) were approved by the local animal welfare committee (Center for Interdisciplinary Research in Biology and College de France) and by the Ethics Committee in Charge of Animal Experimentation (Paris Centre et Sud), and EU guidelines (directive on “The Protection of Animals Used for Scientific Purposes”, 2010/63/EU). Every effort was made to minimize animal suffering and to use the minimum number of animals per group and experiment. Animals were placed in SE or EE (detailed below) under controlled conditions (22 ± 1 °C, 55 ± 5% relative humidity, and 12:12 h light/dark cycle) with food and water provided ad libitum.

Rearing environments

Animals were randomly distributed in two groups: (1) SE or (2) EE for eight weeks. All animals were housed in a 12 h light/dark cycle and litter, food and water were available ad libitum.

Standard housing environment

Cages for SE were standard laboratory cages (47 × 35 × 21 cm) that contained only bedding without complex inanimate and social stimulation.

Enriched housing environment

Based on the standard definition of EE housing (a combination of complex inanimate and social interactions^2,6,7,31), three male rats from the same litter (from 50–60 g, i.e. 22–27 days) were housed for eight weeks in large cages (80 × 57 × 21 cm) with a running wheel, to promote physical exercise at will, and at least 3–5 differently shaped objects (tunnels, shelters, stairs, boxes, movable balls, plastic toys, nesting materials). Objects were replaced every two days during the eight weeks to ensure continuous novelty and complexity. In addition to the running wheel, caution was taken to provide at least one object aiming at decreasing stress (tunnel or shelters with various shapes and textures with increasing size and diameter according to rodent development) and another object promoting physical activity at will and exploration (toys, balls, tanks of hidden food). We used toys and balls that displayed various shapes/diameters, textures, or colours. Running wheels were randomly removed from the cage for one day every 10 days to promote novelty. Rats were exposed continuously to EE for eight weeks before evaluation of synaptic plasticity.

In vivo single-unit intracellular recordings

Animal preparation

Animals (weighting 275–300 g, P_80-90) were initially anaesthetized using chloral hydrate (420 mg/kg, i.p.) (Sigma-Aldrich, Saint-Quentin Fallavier, France) and placed in a stereotaxic frame (Unimecanique, Asniere, France) with their heads secured horizontally. The skull was exposed, and two 3-mm burr holes were drilled over the right dorsal striatum and the ipsilateral somatosensory cortex. Rats were continuously monitored using the electrocardiogram to ascertain that vital signs were within physiological range. Body temperature was maintained at 36.5 °C for the entire experiment with a homeothermic blanket. Anaesthesia maintenance was ensured by continuous infusion (i.p.), on demand, of chloral hydrate using a peristaltic pump.

Deep anaesthesia experiments

To obtain a deep level of anaesthesia, continuous infusion of chloral hydrate was administered at 60 mg/kg/h (turned on one hour after induction). Proper depth of anaesthesia was assessed regularly by testing the heart rate, spontaneous electrocorticogram (ECoG) activity (slow oscillatory pattern), the lack of response of mild hind paw pinch, and the lack of vibrissae movement. Spontaneous ECoG activity was recorded using a low impedance (~60 kΩ) silver electrode placed on the dura above the somatosensory cortex and a reference electrode inserted in a muscle at the opposite side of the head. Surface cortical signals were amplified by a differential AC amplifier (Model 1700; A-M Systems), filtered at 10 kHz (CED Micro 1401, Cambridge Electronic Design).

Light anaesthesia experiments

To ensure a light level of anaesthesia, continuous infusion of chloral hydrate was set at 30–40 mg/kg/h and animals were placed in painless contention. For this purpose, after surgery, the head was maintained by a metal bar rigidly fixed to the stereotaxic frame and anchored on the skull with dental cement; the ear bars and mouth piece were then removed. In this case, the suitable level of anaesthesia was adjusted to have no large delta waves with a small amplitude, fast and tonic ECoG activity.

In vivo intracellular (sharp pipette electrode) recordings

Intracellular recordings of MSNs were performed using glass microelectrodes filled with 1 M K-acetate (resistance measured in the brain between 60 and 100 MΩ) and mounted on a piezo-controlled microdrive (Burleigh Instruments, Fishers, NY, USA). Recordings were performed in the dorsal striatum, at the same anteriority as the cortical stimulation, in a region directly targeted by the afferents from the somatosensory motor cortex (stereotaxic coordinates: 0.5–3.5 mm posterior to bregma, 4.2–4.8 mm lateral to the midline and 3–5.5 mm ventral to the cortical surface). Once the electrode was placed, to obtain long-duration stable intracellular recordings, the craniotomy was filled with low melting point paraffin and the cistern was drained.

All recordings were obtained using an Axoclamp-2B amplifier (Molecular Devices, San Jose, CA, USA) configured in current-clamp mode and the bridge was balanced manually online (−0.3 nA, 50 ms current pulses). Impalements of neurons were considered successful when the membrane potential (Vm) was at least −60 mV and spike amplitude >50 mV. Current-clamp recordings were filtered at 10 kHz. Electrical activity was acquired and directly sampled at 10 kHz with a CED Micro1401 (Cambridge Electronic Design, Cambridge, UK) and analysed off-line with the Spike2 software (Cambridge Electronic Design, Cambridge, UK). MSNs were distinguished from interneurons based on passive and active membrane properties³² (see Fig. 1). Ri of neurons was assessed with the mean steady-state voltage deflections during hyperpolarizing current pulses (−0.3 nA, 50 ms duration, every 5 s) applied intracellularly through the recording electrode. Current-voltage relationships were obtained by injecting hyperpolarizing and depolarizing current pulses through the microelectrode (increasing step of 0.1 nA from −0.6 to 0.6 nA). Subsequently, some of the recorded neurons were identified morphologically (see Methods below).

STDP induction protocols

Electrical stimulations of the cerebral cortex were performed with a concentric bipolar electrode (300 µm diameter, 300 µm tip-barrel distance) (Phymep, Paris, France) placed in layer 5 of the somatosensory cortex (stereotaxic coordinates: −1.8 mm to bregma, 5.8–6 mm to the midline and 3.5 mm ventral to the dura mater). Electrical stimulations (100 µs) were monophasic at constant current (Pulsemaster A300, WPI, Stevenage, UK). Current pulse intensity (0.1–1 mA) was adjusted to evoke striatal subthreshold excitatory post-synaptic potentials (EPSPs) ranging from 5 to 20 mV. Repetitive control stimuli were applied at 0.2 Hz. At the end of each in vivo recording session, we verified the cortical localization of the stimulating electrode. The position of the electrode was marked by electrolytic lesion by passing a current of ±50 mA during 1 s, which was then observed on histological sections (50 µm) after safranine staining. The control baseline recording consisted of at least 50–60 responses to cortical stimuli delivered at 0.2 Hz. STDP induction protocols of pre- and post-synaptic stimulation pairings (100–120 times at 1 Hz) with a time shifting (Δt_STDP) of several milliseconds, corresponding to the duration between the stimulation artefact and the peak of the post-synaptic spike. Pre-synaptic stimulations corresponded to cortical stimulations and post-synaptic stimulations to a depolarizing step current (30 ms duration) intracellularly injected through the recording electrode (the intensity of this current step, 0.2–29 nA, was adjusted to evoke 1–3 action potentials in the MSN). We chose somatic current injection to evoke post-synaptic action potentials because somatosensory stimulations (vibrissae) hardly evoke MSN firing under anaesthesia³³ (data not shown). After STDP pairings, MSNs were recorded with 0.2 Hz cortical stimuli for 30–60 minutes. Long-term synaptic efficacy changes were measured after 50 min. Input resistance (assessed with hyperpolarizing current of −0.3 nA for 50 ms) and Vm were monitored throughout the experiment (both measured every 5 sec) and variation >20% led to exclusion of the experiment.

Electrophysiological data analysis

Off-line analysis was performed using the Spike2 software (Cambridge Electronic Design, Cambridge, UK) and Igor-Pro 6.0.3 (Wavemetrics, Lake Oswego, OR, USA). The strength of the synaptic transmission was measured as the EPSP slope. A linear fit to the ascending phase of the EPSP was calculated from a time corresponding to 10% of the EPSP amplitude to the top. Throughout the recording, every two minutes, 24 successive EPSPs were individually measured and normalized to the mean of the baseline. The 24 normalized EPSP slopes were then averaged and expressed as mean ± SEM. Synaptic efficacy changes measured after 50 min of the STDP induction protocol were classified as either tLTP or tLTD when the mean normalized EPSP slope (corresponding to the last 4–5 min of the recording) was significantly different from the control baseline. For each cell, the value reported on the graphs represents the mean of the last 50–60 EPSP slope measurements. Note that, in parallel, the amplitude of EPSPs (from the basal Vm to the EPSP peak) and the EPSP area (integral) were also measured. In all cases, results (tLTP, tLTD and absence of plasticity) were similar with the estimated amplitude, area and slope of EPSPs (see Fig. 2h for correlation between EPSP amplitude and slope). When considered altogether (n = 85 neurons), correlations between EPSP slopes and either peak amplitudes or areas were significant: r² = 0.55 (p < 0.0001) and r² = 0.33 (p < 0.0001), respectively.

Spectral analysis of ECoG potentials was performed by applying Fast Fourier Transforms using Spike2 (Cambridge Electronic Design, Cambridge, UK).

Statistical analysis was performed using the Prism 5.0 software (San Diego, CA, USA). All results were expressed as mean ± SEM. Statistical significance was assessed using the Student’s unpaired/paired t-tests or one-way ANOVA for variables normally distributed (Vm, Vm SD, VM UP and Down states, firing threshold, action potential amplitude and number of action potentials per pulse). However, to assess differences in variables with non-normal distribution (Ri, rheobase, EPSP amplitude, amplitude of LTP/LTP/no plasticity and %EPSPS slope vs basal), Wilcoxon matched-pairs signed rank test or Kruskal-Wallis test were used. The Kolmogorov-Smirnov test was used for assessment of normality. Linear regression analysis was conducted for correlations (SigmaStat version 3.5, Systat Software). The level of statistical significance was set at p < 0.05.

We measured the mean Vm before each stimulation during the baseline, during and after STDP pairings. To do so, we detected stimulations using two thresholds (one for the potential and one for its derivative). When a stimulation was detected, we measured the mean potential values over 20 ms (starting from 1 ms preceding stimulation). Then, we computed for each experiment the mean and variance of Vm before stimulations, in the three different phases. For post-STDP pairings, potentials were measured at the end of the recordings over five minutes. The algorithm was implemented in Python (2.7 and 3.6), using the anaconda suite (Anaconda Software Distribution, Computer software Version 2–2.4.0. Nov 2016, Web. https://anaconda.com).

Spearman correlation tests were conducted between the mean/variance of Vm during the three experimental phases and the relative synaptic efficacy changes. Pearson correlations were also computed for Vm in the five minutes baseline preceding STDP pairings and in the last five minutes of the recordings (post-STDP pairings). We report the p-values in Supplementary Figs. 1–4. Statistical analysis was performed using the scipy.stats Python library.

Whole-cell patch-clamp recordings in acute brain slices

Brain slice preparation

Horizontal brain slices (thickness 330 µm) from adult (P65-90) Sprague-Dawley male rats (Charles River), preserving corticostriatal connections between somatosensory cortex layer 5 and dorsolateral striatum³⁴, were prepared as previously described¹⁷ by using a vibrating blade microtome (VT1200S, Leica Microsystems, Nussloch, Germany). Brains were sliced in an ice-cold cutting solution (125 mM NaCl, 2.5 mM KCl, 25 mM glucose, 25 mM NaHCO₃, 1.25 mM NaH₂PO₄, 2 mM CaCl₂, 1 mM MgCl₂, 1 mM pyruvic acid) bubbled with 95% O₂/5% CO₂.

Patch-clamp electrophysiological recordings

Patch-clamp recordings were performed as previously described^16,17,34. Briefly, borosilicate glass pipettes with 4–6 MΩ resistance were used for whole-cell recordings (in mM): 122 K-gluconate, 13 KCl, 10 HEPES, 10 phosphocreatine, 4 ATP-Mg, 0.3 GTP-Na, 0.3 EGTA (adjusted to pH 7.35 with KOH). The composition of the extracellular solution was (mM): 125 NaCl, 2.5 KCl, 25 glucose, 25 NaHCO₃, 1.25 NaH₂PO₄, 2 CaCl₂, 1 MgCl₂, 10 μM pyruvic acid bubbled with 95% O₂ and 5% CO₂. Signals were amplified using an EPC10-2 amplifier (HEKA Elektronik, Lambrecht, Germany). All recordings were performed at 34 °C using a temperature control system (Bath-controller V, Luigs & Neumann, Ratingen, Germany) and slices were continuously superfused at 2–3 ml/min with the extracellular solution. Current- and voltage-clamp recordings were sampled at 10 kHz, with the Patchmaster v2x32 program (HEKA Elektronik).

STDP induction protocols

According to previous studies^16,17,34, electrical stimulations were performed with a concentric bipolar electrode (Phymep, Paris, France) placed in layer 5 of the somatosensory cortex and were monophasic at constant current (ISO-Flex stimulator, AMPI, Jerusalem, Israel). Currents were adjusted to evoke 50–200 pA EPSCs. Repetitive control stimuli were applied at 0.1 Hz. STDP protocols consisted of pairings of pre- and post-synaptic stimulations (at 1 Hz) at a fixed Δt_STDP. Pre-synaptic stimulations corresponded to cortical stimulations and the post-synaptic stimulation to an action potential evoked by a depolarizing current step (30 ms duration) in MSNs. MSNs were recorded for 10 min during baseline and for at least 60 min after STDP protocol; long-term synaptic efficacy changes were measured after 50 min. The amplitudes of 30 successive EPSCs were individually measured and the average was calculated. Variation of input and series resistance (Ri and Rs) above 20% led to exclusion of the experiment.

Trichloroethanol treatment

After recording a baseline in control conditions (10 min), trichloroethanol (5 mM, directly diluted in the extracellular solution) was bath-applied. After 10 min (required time to allow for total perfusion of the drug), a baseline with trichloroethanol was recorded for 10 min before application of the STDP protocol. Trichloroethanol was continuously applied until the end of the experiment.

Patch-clamp data analysis

Analysis was performed off-line using Fitmaster (Heka Elektronik) and Igor-Pro 6.0.3 (Wavemetrics, Lake Oswego, OR, USA). All results were expressed as the mean ± S.E.M. and “n” refers to a single-cell experiment from a single slice. Statistical analysis was performed with the Prism 5.0 software (GraphPad Software Inc., CA, USA) and statistical significance was assessed in Wilcoxon signed rank test using the indicated significance threshold (p).

Immunohistochemistry

In a subset of experiments, intracellular glass micropipettes were filled with 1.5% biocytin (Sigma), dissolved in 2 M potassium acetate. MSNs were passively filled during at least 80 min of recordings. At the end of the electrophysiological experiment, rats were deeply anaesthetised (sodium pentobarbital, 150 mg⁄kg i.p.) and transcardially perfused with saline followed by 4% ice-cold paraformaldehyde in 0.1 M phosphate buffer. Brains were extracted and, following 2 h in the fixative solution, were transferred to 30% sucrose. Brains were then cut in frontal 50-µm sections using a freezing microtome and slices were maintained in 0.1 M potassium-PBS (pH = 7.4). To recover the recorded cell and visualize the biocytin-filled neurons, avidin-biotin-horseradish peroxidase was used (ABC Elite peroxidase kit; Vector Laboratories, Burlingame, CA, USA) according to manufacturer’s instructions.

Results

Properties of corticostriatal transmission in vivo

To study the effect of EE on corticostriatal STDP, we recorded MSNs in vivo from rats grown in SE or EE with various anaesthetic regimes (Fig. 1a; see Methods). We performed in vivo intracellular recordings in current-clamp mode of MSNs located in the dorsolateral striatum from adult rats (P_80-90) with stimulation in the somatosensory cortex (layer 5) (n = 85) (Fig. 1b,c). We performed sharp electrode intracellular recordings because this technique ensures limited cytoplasm washout through the recording pipette, required for the long-duration recordings. Chloral hydrate anaesthetised rats were used to obtain stable intracellular recordings along time; because of the anaesthesia, cortical inputs were electrically stimulated to evoke striatal EPSPs. The recording session started when the depth of anaesthesia (deep or light) was ensured based on the power spectrum of surface ECoG activity (see example for deep anaesthesia in Figs. 1c). MSNs were electrophysiologically identified, and distinguished from the striatal interneurons, based on passive and active membrane properties^32,35, such as hyperpolarized resting Vm (−84 ± 0.8 mV, n = 85), low input resistance (34 ± 2 MΩ), inward rectifying I/V relationship and long-latency spike discharge at rheobase (Fig. 1d). Post-recording morphological analysis performed in a subset of experiments confirmed the identity of the recorded MSNs (n = 5) (Fig. 1c). Stimulation of the ipsilateral corticostriatal afferents evoked EPSPs in MSNs with short latency (3.2 ± 0.1 ms, n = 85) and latency SD < 1 ms (0.25 ± 0.01 ms, n = 85) indicating a monosynaptic feature of this transmission (Fig. 1e). Once the corticostriatal transmission occurred, no failure was observed in MSNs, denoting a reliable and efficient transmission.

To evaluate long-term synaptic weight changes, only long-duration recordings were included in this study. First, we assessed the EPSP slope stability during 50 min recordings (by applying 0.2 Hz cortical test stimulations) in 4 MSNs. As exemplified in Fig. 1f, no significant variation in EPSP slopes was observed along time (basal EPSP slope: 100 ± 6% of the baseline; after 20 min: 108 ± 5%; after 50 min: 103 ± 5%; p = 0.5210); note the stable time course of Ri and Vm. Overall, as shown in the summary time course (Fig. 1f), we did not observe significant variation in EPSP slopes along time (mean value of the EPSP slope recorded after 50 min: 95 ± 2%, p = 0.066, n = 4; 4/4 cells showed not significant change in synaptic weight); none of the points was significantly different from the baseline average (the first five minutes) (p = 0.0767, Kruskal-Wallis test). We thus ensured that long-duration intracellular recordings do not affect significantly the EPSP slope, make it an appropriate technique for characterizing in vivo STDP.

In vivo STDP in deeply anaesthetised rats grown in standard housing

We examined the influence of the temporal relationship between MSN firing and activation of corticostriatal afferents on the induction of synaptic plasticity (STDP), in adult rats grown in SE and deeply anaesthetised. Depth of anaesthesia was continuously assessed by recording spontaneous ECoG activity and was adjusted until the power spectral analysis indicated a deep level of anaesthesia (dominant frequency in the 1–3 Hz range, as exemplified in Fig. 2a). Under these conditions, recorded MSNs (n = 35) displayed an average Vm of −84 ± 1 mV, input resistance of 38 ± 3 MΩ (Table 1) and showed Vm periodic transitions between up and down states (magnitude of the fluctuations: 19 ± 0.8 mV) (Fig. 2a, Table 1 and Supplementary Fig. 1). We applied STDP pairings consisting of 100 stimulations at 1 Hz of the somatosensory cortex paired with post-synaptic suprathreshold depolarization (evoking 1–3 spikes) with a time shifting (Δt_STDP). Δt_STDP < 0 refers to post-pre pairings (post-synaptic stimulation precedes pre-synaptic stimulation), whereas Δt_STDP > 0 refers to pre-post pairings (pre-synaptic stimulation precedes post-synaptic stimulation) (Fig. 2b).

Table 1 Passive and active membrane properties and characteristics of corticostriatal synaptic evoked-responses of in vivo recorded MSNs.

Full size table

In adult rats grown in SE and deeply anaesthetised, STDP pairings induced mainly a dominance of tLTD within a wide Δt_STDP range (−100 < Δt_STDP < +100 ms) together with a high rate of absence of plasticity (Fig. 2).

Post-pre pairings (−100 < Δt_STDP < 0 ms), among 23 successful experiments, induced 9 tLTD, 9 absences of plasticity and 5 tLTP. Figure 2c shows an example of tLTD induced by 100 post-pre pairings (Δt_STDP = −10 ms), where the mean baseline EPSP slope was 2.00 ± 0.06 mV/ms before pairings, and decreased by 65% to 1.32 ± 0.05 mV/ms one hour after pairings; note the stable time courses of Ri and Vm. Figure 2d shows an example of tLTP induced by 100 post-pre pairings (Δt_STDP = −21 ms), where the mean baseline EPSP slope was 0.87 ± 0.04 mV/ms before pairings, and increased by 128% to 1.11 ± 0.07 mV/ms one hour after pairings.

With pre-post pairings, we performed 12 successful experiments, including 6 tLTD and 6 absences of plasticity. More specifically, we observed 60% of tLTD and 40% of absence of plasticity (n = 10) for 0 < Δt_STDP < +100 ms, and two absences of plasticity for Δt_STDP > +100 ms. Figure 2e shows an example of tLTD induced by 100 pre-post pairings (Δt_STDP = +29 ms), where the mean baseline EPSP slope was 2.47 ± 0.12 mV/ms before pairings and decreased by 69% to 1.71 ± 0.15 mV/ms one hour after pairings. A total of 100 pre-post pairings with large Δt_STDP (Δt_STDP > +100 ms, n = 2) did not induce any plasticity, as shown in Fig. 2f (Δt_STDP = +130 ms, mean baseline EPSP slope before pairings was 0.95 ± 0.55 mV/ms and 0.98 ± 0.46 mV/ms one hour after pairings; variation 3%).

Taken together, there was no significant change in synaptic weight after post-pre pairings (95 ± 5%, p = 0.3611, n = 23), but tLTD was observed with pre-post pairings (88 ± 4%, p = 0.0278, n = 12). However, if we considered separately tLTP and tLTD, post-pre pairings induced mainly tLTD (mean value of the EPSP slope recorded 60 min after STDP protocol: 71 ± 5%, n = 9, p = 0.0089) and pre-post pairings induced exclusively tLTD (77 ± 3%, n = 6, p = 0.0340) (Fig. 2g). The temporal window of tLTD induction was large, spanning over 200 ms (−100 < Δt_STDP < +100 ms). Beyond Δt_STDP ±100 ms, no significant plasticity was induced (101 ± 1%, n = 3, p = 0.7500).

In addition to tLTD dominance, it should be noted that almost half of the STDP pairings did not induce significant plasticity (failure rate: 43%, n = 35). Indeed, 39% (n = 23) and 50% (n = 12) of the post-pre and pre-post pairing experiments, respectively, failed to induce long-term synaptic efficacy changes (post-pre pairings: 99 ± 3%, n = 9, p = 0.8583 and pre-post pairings: 99 ± 3%, n = 6, p = 1.000).

In some cases (22%, 5/23 post-pre pairing experiments), we observed tLTP for post-pre pairings in a narrow Δt_STDP range (−30 < Δt_STDP < 0 ms) (Fig. 2d). Among the 14 experiments performed within −30 < Δt_STDP < 0 ms, we observed a mixture of plasticity with similar occurrence (36%) between tLTD (67 ± 8%, n = 5, p = 0.0179) and tLTP (132 ± 6%, n = 5, p = 0.0425), as well as no plasticity (28%) (105 ± 3%, n = 4, p = 0.2500) (Fig. 2g). Interestingly, we found a significant correlation (r² = 0.41) between the number of postsynaptic action potentials evoked during the post-pre pairings and the polarity of plasticity (for −30 < Δt_STDP < 0 ms). Indeed, more than one post-synaptic spike favoured induction of tLTP (2.4 ± 0.2 spikes, n = 3), whereas one spike was associated to tLTD expression (1.2 ± 0.2 spikes, n = 5) (p = 0.0323) (Fig. 2i). This correlation between the number of post-synaptic spikes during the STDP pairings and the polarity of plasticity was found exclusively for narrow negative Δt_STDP (i.e. −30 < Δt_STDP < 0 ms), since for more negative Δt_STDP (−100 < Δt_STDP < −30 ms) and positive Δt_STDP (0 < Δt_STDP < +100 ms), only tLTD or absence of plasticity was observed, independent of the number of post-synaptic spikes (range from 1 to 3 spikes; r² = 0.65).

It was reported in ex vivo studies that induction of STDP depends on EPSP magnitude (resulting from pre-synaptic stimulation)³⁶. Here, there was no correlation between tLTD and tLTP induction after post-pre pairings with the EPSP amplitudes (r² = 0.096), Vm (r² = 0.0001), Ri (r² = 0.0058) or rheobase (r² = 0.2456; tLTP: 0.54 ± 0.04 nA, n = 5, and tLTD: 0.43 ± 0.05 nA, n = 9; p = 0.1758) of the recorded MSNs (n = 14). We investigated whether Vm during baseline, STDP pairings or during the last five minutes of recordings influences the polarity of plasticity and magnitude (Supplementary Fig. 1). In SE and deep anaesthesia conditions, we did not find any correlation between Vm (mean or variance) and plasticity output, except for the magnitude of tLTD induced by pre-post pairings. Plots of Vm during the STDP pairings are illustrated for each representative experiment (Fig. 2c–f). In conclusion, Vm fluctuations (including during the STDP pairings) do not account for the plasticity polarity (Supplementary Fig. 1).

Thus, in in vivo deeply anaesthetised adult rats grown in SE, we mainly observed tLTD induced with low success rate in a wide Δt_STDP range (~200 ms), in contrast to what has been described in ex vivo corticostriatal STDP experiments showing that bidirectional STDP was induced in a much shorter temporal window (~60 ms: −30 < Δt_STDP < +30 ms) with lower failure rate (<15%)^{16,17,34,37,38,39,40}.

Anaesthesia with chloral hydrate favours tLTD

The previous experiments were performed in anaesthetised adult animals. In contrast, ex vivo studies, which widely reported bidirectional STDP centred on Δt_STDP = 0 in various brain structures¹¹, were generally performed in juvenile animals without anaesthetics. Thus, we tested whether age and anaesthesia status may influence STDP. For this purpose, we performed experiments in brain slices from P_65-90 rats, because it is not possible to perform in vivo long-duration (i.e. >80 min) intracellular recordings in non-anaesthetised animals.

Using whole-cell patch-clamp recordings in horizontal brain slices (Fig. 3a,b), we found bidirectional STDP in a restricted time window (~60 ms). As previously reported for juvenile rodents at corticostriatal synapses^34,38,39,41, we induced bidirectional STDP centred on Δt_STDP = 0 ms with 100 pairings (n = 40). Figure 3c,d show examples of tLTP and tLTD induced by 100 post-pre and pre-post pairings, respectively. Post-pre pairings (−30 < Δt_STDP < 0 ms) induced tLTP (146 ± 15%, p = 0.0004, n = 9; success rate: 69%), whereas pre-post pairings (0 < Δt_STDP < +30 ms) induced tLTD (67 ± 5%, p = 0.0039, n = 9; success rate: 90%) (Fig. 3e). Pairings for −60 < Δt_STDP < −35 ms and +30 < Δt_STDP < +40 ms did not induce plasticity (105 ± 5, p = 0.0823, n = 5, and 101 ± 6, p = 0.6589, n = 7, respectively) (Fig. 3e). Thus, polarity and magnitude of STDP were similar between juvenile and adult animals. We recorded STDP in the absence of GABA_A receptor antagonist, because we previously showed that GABA operates as a Hebbian/anti-Hebbian switch at corticostriatal synapses^16,17; thus anti-Hebbian polarity is preserved, as observed in vivo at corticostriatal synapses⁴². Anaesthesia affects neuronal properties and excitation/inhibition balance^43,44. We then tested whether anaesthesia would affect STDP features. For this purpose, we studied the effect of trichloroethanol, the major metabolite of chloral hydrate responsible for anaesthesia⁴⁵ and the anaesthetic used to perform the in vivo recordings in this study. We first investigated the effects of bath-applied trichloroethanol (5 mM) on corticostriatal transmission and found a marked decrease in the amplitude of EPSC (by 47.4 ± 6.2%, p < 0.0001, n = 17). We then investigated the effects of trichloroethanol on STDP and observed a unidirectional STDP in which only tLTD was induced. As exemplified in Fig. 3f,g, post-pre and pre-post pairings induced tLTD. To summarize, 100 post-pre pairings induced tLTD (65 ± 5%, p = 0.0020, n = 10; success rate: 100%) as well as pre-post pairings (48 ± 7%, p = 0.0425, n = 5; success rate: 100%) (Fig. 3h). In addition, Δt_STDP was considerably larger under trichloroethanol for both post-pre and pre-post pairings (−100 < Δt_STDP < +100 ms) (Fig. 3h) in comparison with control conditions (−30 < Δt_STDP < +30 ms) (Fig. 3e). Therefore, in corticostriatal brain slices, trichloroethanol treatment prevents tLTP induction to the benefit of tLTD with increased Δt_STDP.

Light anaesthesia status favours in vivo bidirectional plasticity

The use of long-duration intracellular recordings (sharp pipette electrode) prevents any investigation on freely-moving animals because of mechanical instability. In order to reduce, as much as possible, the level of anaesthesia, we performed long-duration intracellular recordings in lightly anaesthetised rats in painless contention; in this series of experiments rats were grown in SE. The light anaesthesia state was controlled by recording spontaneous ECoG activity and was adjusted until the ECoG spectral analysis showed a dominant frequency ~ 3–5 Hz range associated with faster waves (Fig. 4a). In parallel, the up and down states of the MSN Vm observed in deeply anaesthetised rats disappeared under light anaesthesia (down to up fluctuations of 16 ± 1 mV) (Table 1). In these conditions, we obtained long-duration recordings in 14 MSNs.

In rats reared in SE, we observed a different STDP map in light anaesthesia compared to deep anaesthesia. Indeed, although tLTD with a high rate of failure of plasticity induction was still dominant, we found that few tLTP could be induced for a restricted Δt_STDP without overlapping with tLTD domain of expression (for −100 < Δt_STDP < +100 ms: success rate of tLTD: 55%, tLTP: 18% and no plasticity: 27%; n = 11) (Fig. 4d). Moreover, post-pre pairings with −50 < Δt_STDP < 0 ms (n = 4) induced tLTD (76 ± 0.3%; success rate: 75%), whereas post-pre pairings with −100 < Δt_STDP < −50 ms (n = 3) induced tLTP (131 ± 12%, n = 2; success rate: 67%) (Fig. 4d). Thus, with post-pre pairings a bidirectional STDP was observed, with tLTD and tLTP occurring in distinct Δt_STDP. As exemplified in Fig. 4b,c, post-pre pairings (Δt_STDP = −48 ms) induced tLTD (mean baseline EPSP slope, 2.66 ± 0.09 mV/ms, decreased by 77%, to 2.05 ± 0.10 mV/ms, one hour after pairing), whereas tLTP was induced for larger Δt_STDP (for Δt_STDP = −87 ms, mean baseline EPSP slope, 0.80 ± 0.05 mV/ms, increased by 153%, to 1.21 ± 0.08 mV/ms, 26 min after pairing). Pre-post pairings for 0 < Δt_STDP < +100 ms (n = 5) triggered tLTD (79 ± 4%, n = 3; success rate: 60%) (Fig. 4d). Beyond Δt_STDP = ±100 ms, no significant plasticity was observed (102 ± 5%, p = 1.0000, n = 3).

Thus, under light anaesthesia bidirectional STDP was observed on the post-pre pairing side, while tLTD still dominated in large Δt_STDP. We did not find significant difference between the polarity of plasticity and the number of post-synaptic spikes (p = 0.3626) (Fig. 4e). We did not find significant correlation between Vm (mean or variance) and plasticity output, (except for the expression of tLTP induced by post-pre pairings, which could be biased due to the low numbers of tLTP) (Supplementary Fig. 2). Plots of Vm during the STDP pairings are illustrated for representative experiments (Fig. 4b,c).

STDP recorded in deep versus light anaesthetised rats grown in SE display common features with overall tLTD dominance occurring in wide Δt_STDP (~200 ms). However, a bidirectional trend of STDP (i.e. tLTP and tLTD occurring in distinct Δt_STDP) emerges in light anaesthesia, whereas in deep anaesthesia tLTP could be also observed, but sharing the same Δt_STDP as tLTD. We found a similar failure rate of plasticity induction between deep and light anaesthesia conditions (42 vs 43%) for −150 < Δt_STDP < +150 ms. When restricted to −100 < Δt_STDP < +100 ms, a higher failure rate was observed in deep than in light anaesthesia conditions (37% vs 27%).

Environmental enrichment promotes bidirectional in vivo plasticity (centred on Δt_STDP = −50 ms)

Acquisition of a task involving procedural learning has been associated with an increased AMPA/NMDA ratio, i.e. LTP, at corticostriatal synapses^{25,27,28,29,30,46}. Due to increased learning and memory performance reported in rodents raised in EE^1,2,3,4,5, we tested whether rearing in EE could promote tLTP, as opposed to the tLTD dominance (and the high failure rate of plasticity) observed in rats grown in SE. To this purpose, 19 MSNs were recorded in vivo in EE rats under deep anaesthesia. The level of anaesthesia was adjusted until the ECoG spectral analysis showed a high-power dominant frequency in the ~1–3 Hz range (Fig. 5a).

Rats grown in EE and SE exhibited different STDP maps. First, STDP post-pre pairings induced long-term synaptic efficacy changes with a success rate of 79% (n = 14), denoting less failure in plasticity induction than in SE rats recorded under deep or light anaesthesia (success rate: 61%, n = 23 vs 71%, n = 7, respectively). In vivo intracellular recordings (n = 19) performed in rats grown in EE revealed a bidirectional STDP centred on Δt_STDP = −50 ms (Fig. 5). Indeed, post-pre pairings with −50 < Δt_STDP < 0 ms (n = 9) induced mainly tLTD (79 ± 3%, n = 6, p = 0.0355) or an absence of plasticity (93 ± 2%, n = 2), whereas for a wider temporal window (−100 < Δt_STDP < −50 ms) tLTP was exclusively observed (151 ± 13%, n = 4, p = 0.0467) (Fig. 5d). As shown in Fig. 5b,c, post-pre pairings (Δt_STDP = −24 ms) induced tLTD (mean baseline EPSP slope, 1.33 ± 0.05 mV/ms, decreased by 78%, to 1.04 ± 0.07 mV/ms, one hour after pairing), as well as tLTP (Δt_STDP = −89 ms) (mean baseline EPSP slope, 0.62 ± 0.03 mV/ms, increased by 172%, to 1.07 ± 0.06 mV/ms, one hour after pairing). In this set of experiments, the occurrence of tLTP or tLTD was not dependent on the number of post-synaptic spikes emitted during the STDP protocol (p = 0.4963) (Fig. 5e). While bidirectional STDP was observed for post-pre pairings, plasticity was hardly elicited (94 ± 5%, n = 5, p = 0.2785) for pre-post pairings (0 < Δt_STDP < +150 ms); among these 5 MSNs, two tLTD were induced (Fig. 5d). We did not find a correlation between Vm (mean or variance) and plasticity output (Supplementary Fig. 3). Plots of Vm during the STDP pairings are illustrated for representative experiments (Fig. 5b,c).

In EE rats, STDP exhibited a bidirectional STDP centred on Δt_STDP = −50 ms, i.e. strictly oriented on either side of −50 ms with distinct Δt_STDP for tLTP (−100 < Δt_STDP < −50 ms) and tLTD (−50 < Δt_STDP < 0 ms). As pre-post pairings mainly failed inducing plasticity, the temporal window of plasticity induction was restricted to post-pre pairings and spanned over 100 ms, i.e. half the width of STDP observed in SE rats. These results indicate that EE promotes bidirectional STDP, in distinct Δt_STDP, centred around −50 ms in a shorter Δt_STDP and with a higher success rate than STDP observed in SE rats.

Environmental enrichment associated with light anaesthesia promotes bidirectional STDP (centred on Δt_STDP = 0 ms)

We next tested the combined effects of EE and light anaesthesia by recording long-term synaptic efficacy changes in 18 MSNs. As mentioned earlier, the proper level of anaesthesia was assessed according to recordings of ECoG activity and was adjusted until the ECoG spectral analysis showed a dominant frequency ~3–5 Hz range (Fig. 6a).

In these conditions, we found a bidirectional STDP centred on 0 ms, suggesting that tLTP and tLTD were induced by distinct pairing polarity: tLTP and tLTD were triggered by post-pre and pre-post pairings, respectively. Indeed, post-pre pairings (−100 < Δt_STDP < 0 ms) induced mainly tLTP (140 ± 14%, p = 0.0313, n = 6), whereas pre-post pairings (0 < Δt_STDP < 100 ms) triggered exclusively tLTD (75 ± 4%, p = 0.0425, n = 5) (Fig. 6). A few tLTDs were also observed for post-pre pairings (−100 < Δt_STDP < 0 ms, 74 ± 2%, n = 2). Figure 6b shows an example of tLTP induced by 100 post-pre pairings (Δt_STDP = −15 ms); the mean baseline EPSP slope was 1.44 ± 0.10 mV/ms and increased by 175% to 2.52 ± 0.20 mV/ms one hour after pairings. Pre-post pairings induced only tLTD as exemplified in Fig. 6c; 100 pre-post pairings (Δt_STDP = +12 ms) induced tLTD, where the mean baseline EPSP slope was 2.57 ± 0.10 mV/ms before pairings and decreased by 66% to 1.70 ± 0.07 mV/ms one hour after pairings.

Here, the occurrence of tLTP or tLTD was not dependent on the number of post-synaptic spikes emitted during the STDP protocol (p = 0.3206) (Fig. 6e). We did not find a correlation between Vm (mean or variance) and plasticity output (Supplementary Fig. 4). Plots of Vm during STDP pairings are illustrated for representative experiments (Fig. 6b,c).

Beyond Δt_STDP = ± 100 ms no significant plasticity was observed (88 ± 8%, n = 3, p = 0.3248). The success rate of plasticity induction was increased in EE rats recorded under light anaesthesia; 87% (n = 15) for −100 < Δt_STDP < +100 ms compared to other conditions described earlier (SE rats under deep or light anaesthesia or EE rats under deep anaesthesia). Moreover, the failure rate of plasticity induction dropped to null for tLTD induced by pre-post pairings (0 < Δt_STDP < 100 ms, n = 5). For post-pre pairings, the results were more complex. Indeed, the failure rate of plasticity induction was considerably reduced in EE rats under light anaesthesia (25%, n = 10) with 50% of tLTP, 25% of tLTD and 25% absence of plasticity (Fig. 6d). Therefore, EE conditions coupled to light anaesthesia allow occurrence of an anti-Hebbian bidirectional STDP, as reported in vitro without blockade of GABA_A transmission^16,17.

Comparison of STDP in rats reared in SE or EE, and recorded in deep or light anaesthesia

Differences, in terms of plasticity, were observed depending on the four conditions considered here: rats grown in SE or EE and recorded under deep or light anaesthesia (Fig. 7). EE promotes induction of bidirectional asymmetric plasticity, which was not observed in SE rats deeply anaesthetised. Although the light anaesthetic regime (even in rats reared in SE) tends also to allow for the emergence of bidirectional plasticity, this plasticity was not centred on 0 ms since the tLTP/tLTD transition occurred around −50 ms. In contrast to SE conditions, in which tLTD dominates and tLTP occurrence is lower than the failure of plasticity (SE & deep anaesthesia: 47% tLTD, 16% tLTP, 38% no plasticity, n = 32; SE & light anaesthesia: 55% tLTD, 18% tLTP, 27% no plasticity, n = 11), in EE rats (regardless of the anaesthetic regime) tLTP occurrence is larger than the failure rate of plasticity, while tLTD remains stable (EE & deep anaesthesia: 44% tLTD, 28% tLTP, 28% no plasticity, n = 18; EE & light anaesthesia: 47% tLTD, 40% tLTP, 13% no plasticity, n = 15); here, we considered data harvested for −100 < Δt_STDP < +100 ms.

We did not find a significant correlation between basal properties and expression and polarity of plasticity (r² = 0.04, p = 0.1419), input resistance (r² = 0.02, p = 0.3235), rheobase (r² = 3 × 10⁻⁶, p = 0.9712), EPSP amplitude (r² = 0.07, p = 0.5342) (Table 1). For MSNs recorded within 100 < Δt_STDP < +100 ms (SE & deep anaesthesia, n = 32; SE & light anaesthesia, n = 11; EE & deep anaesthesia, n = 18; EE & light anaesthesia, n = 16), there was no significant difference in input resistance (Kruskal-Wallis test, p = 0.0661), rheobase (Kruskal-Wallis test, p = 0.9901) or EPSP amplitude (Kruskal-Wallis test, p = 0.8747), except for Vm (one-way ANOVA, p = 0.0463, SE & deep anaesthesia vs EE & light anaesthesia). As mentioned earlier, there was no correlation between the number of action potentials and plasticity, except for post-pre pairings STDP in SE rats under deep anaesthesia; in this latter case, tLTP was favoured by a higher number (i.e. 2 versus 1) of back-propagating action potentials (Fig. 2i); the number of post-synaptic action potentials was not significantly different across the four experimental conditions (SE & deep anaesthesia 2.0 ± 0.2 (n = 11), SE & light anaesthesia 2.4 ± 0.4 (n = 5), EE & deep anaesthesia 2.2 ± 0.5 (n = 8), EE & light anaesthesia 1.9 ± 0.2 (n = 8), one-way ANOVA, p = 0.7398). Moreover, the evoked amplitude of tLTP and tLTD was not different across conditions (tLTP: SE & deep anaesthesia 132 ± 6%, SE & light anaesthesia 136 ± 17%, EE & deep anaesthesia 150 ± 10%, EE & light anaesthesia 140 ± 14%, Kruskal-Wallis test, p = 0.5776; tLTD: SE & deep anaesthesia 73 ± 3%, SE & light anaesthesia 78 ± 2%, EE & deep anaesthesia 79 ± 2%, EE light anaesthesia 75 ± 3%, Kruskal-Wallis test, p = 0.4976).

Failure rate was high (38%) in SE rats in deep anaesthesia. Interestingly, the occurrence of failure in induced plasticity (tLTP or tLTD) within –100 < Δt_STDP < 100 ms was the lowest in EE rats under light anaesthesia (failure rate: 13%), whereas it was similar between rats grown in SE under light anaesthesia and EE under deep anaesthesia (27 and 28%, respectively) (Fig. 7).

EE or light anaesthesia tended to reduce the failure rate accompanied with the emergence of bidirectional STDP (not centred on 0 ms), whereas EE and light anaesthetic regime diminished the failure rate and favoured bidirectional STDP centred on 0 ms. Light anaesthetic regime (when compared to deep anaesthesia) decreased the failure rate of plasticity, whereas EE (when compared to SE) favoured tLTP and decreased the failure rate of plasticity; tLTD occurrence appeared stable across the four conditions examined here (Fig. 7).

Discussion

In this study, we show that in vivo polarity and characteristics of STDP in the dorsolateral striatum vary as a function of housing conditions (SE vs EE) and the anaesthetic regime. Indeed, for rats housed in SE and recorded under deep anaesthesia, tLTD constitutes the main form of plasticity regardless of the order of pre- and post-synaptic activity. This is in agreement with previous in vivo studies reporting tLTD as the main form of STDP or absence of plasticity at corticostriatal synapses in anaesthetised (urethane) rodents grown in SE^42,47. Here, occasionally some tLTP were observed for post-pre pairings (−30 < Δt_STDP < 0 ms) and were favoured by a higher number of post-synaptic action potentials. It remains to be examined whether these tLTPs are preferentially expressed in striatopallidal MSNs (D₂R-expressing MSNs) than in striatonigral MSNs (D₁R-expressing MSNs). D₂R-MSNs are more excitable than D₁R-MSNs⁴⁸, and they show higher dendritic excitability than D₁R-MSN, allowing back-propagating action potentials to invade more efficiently in distal dendrites in D₂R-MSNs⁴⁹. We found that deep anaesthesia (chloral hydrate) prevented tLTP expression to the benefit of tLTD (i.e. symmetric anti-Hebbian tLTD was observed). Therefore, shifting from deep to light anaesthetic regime in rats grown in SE seems to favour bidirectional STDP for Δt_STDP < 0 ms, but still with a majority of tLTD induction and failure of plasticity; due to the relatively low number of experiments in SE rats under light anaesthesia, further research is required to firmly determine the occurrence of tLTP for post-pre pairings (−100 < Δt_STDP < −50 ms). These findings were clearer when rats were grown in EE, even under deep anaesthesia: we observed STDP quasi-exclusively for post-pre pairings with tLTP and tLTD being expressed in distinct Δt_STDP domains, i.e. −100 < Δt_STDP < −50 ms and −50 < Δt_STDP < 0 ms, respectively. Importantly, when in vivo intracellular recordings were performed in EE rats under light anaesthesia, bidirectional and asymmetric anti-Hebbian STDP was observed: tLTP and tLTD were induced by post-pre and pre-post pairings, respectively. In vivo corticostriatal STDP could be induced in larger Δt_STDP than in brain slices (~150 ms in vivo: −50 < Δt_STDP < +100 ms vs ~70 ms ex vivo: −30 < Δt_STDP < +40 ms)^{34,37,38,39,40}. Interestingly, in SE conditions, regardless of the anaesthetic regime, the occurrence of tLTP is similar (16 and 18%, in deep and light anaesthesia, respectively), whereas in EE the anaesthetic regime displays a greater influence on tLTP expression (28% and 40%, in deep and light anaesthesia, respectively) (Fig. 7). Therefore, this indicates that housing conditions exert a marked influence (larger than the anaesthetic regime) on map plasticity.

Since variability is common in synaptic plasticity, effects of EE on STDP may be variable. Indeed, the effect of EE on STDP is expected to be different depending on the brain area (cortex, hippocampus, cerebellum, striatum), on the various forms of STDP (Hebbian or anti-Hebbian, symmetric or asymmetric, bidirectional or unidirectional) and also on the signalling pathways (for example, NMDA receptors (NMDAR) and/or endocannabinoids)¹¹. Interestingly, NMDAR- and endocannabinoid-mediated STDP are differentially impacted by noisy spike timings (mimicked by jittered pairings): NMDAR-tLTP being susceptible and endocannabinoid-tLTD or -tLTP being robust to jitter⁵⁰. Here, using STDP pairings with fixed Δt_STDP, we did not observe jitter >3 ms. Therefore, it is less likely that (NMDAR)-tLTP could not be observed because of spike jittering. However, under in vivo physiological patterns, we can hypothesize that tLTP would be more difficult to be induced because of large jitters, whereas endocannabinoid-STDP would emerge more easily. The underlying signalling pathways of in vivo striatal tLTP and tLTD remain also to be characterised. Interestingly, an increase in the AMPA/NMDA ratio, a proxy for LTP, has been detected in awake and behaving mice over-trained to accomplish a task involving procedural learning^{25,26,27,28,29,30,46}. In vivo investigation of synaptic plasticity mostly performed in adult and anaesthetised rodents, showed that LTD was easily elicited while LTP was hardly observed. As an illustration, in in vivo anaesthetised mice, corticostriatal tLTP was induced only when combined with electrical stimulation of the dopaminergic neurons of the substantia nigra pars compacta or with pharmacological blockade of GABAergic transmission in the midbrain superior colliculus⁴⁷.

In the neocortex or the hippocampus, several ex vivo studies from animals subjected to EE have reported changes in the excitation/inhibition balance, serotoninergic or cholinergic tones, increase of noradrenaline or BDNF, enhanced LTP and LTD, increase in mEPSCs amplitude and frequency, changes in neuronal excitability or increase in gamma oscillations. It is fair to note that an equivalent amount of studies have shown opposite results or the absence of significant changes for some of the aforementioned parameters^22,51. Nevertheless, there is a consensus concerning the improvement of learning and memory induced by EE exposure^1,22. In line with this, we show here that expression of bidirectional STDP within a short temporal window is favoured by exposure to EE.

Ex vivo long-term plasticity at excitatory synapses is generally examined with pharmacological blockade of GABA_AR-mediated transmission to isolate glutamatergic transmission. We previously showed in striatum that GABA controls polarity of STDP^16,17. Indeed, Hebbian and anti-Hebbian polarities of cortico-striatal STDP have been observed⁴¹ depending on the use (Hebbian STDP^38,39) or not (anti-Hebbian STDP^34,37,40) of GABA_AR antagonists. This is in agreement with in vivo experiments, in which GABA transmission was not blocked (although it should be noted that anaesthesia affects GABAergic tone), showing an anti-Hebbian cortico-striatal STDP⁴² (and the present study). However, corticostriatal Hebbian STDP was elicited with pharmacological manipulation of GABAergic, dopaminergic and adenosine transmission⁴⁷. In these in vivo corticostriatal STDP studies^42,47, the recording duration of MSNs was between 10 and 20 minutes, which remains relatively short for STDP estimation. Indeed, STDP full expression does not generally occur during the first 15 minutes after pairings, and the initial fluctuations of synaptic weights do not necessarily predict long-term plasticity after one-hour recording. Nevertheless, it remains to be determined which STDP-like mechanisms are involved in awake and behaving rodents. It has been proposed that anti-Hebbian STDP would disfavour predictable inputs, keep synapses weak, and would allow novel sensory inputs to be better represented^14,52. Therefore, anti-Hebbian STDP could be a crucial requirement for striatum, which acts as a coincident detector of distributed patterns of cortical and thalamic activity.

EE reduces inhibitory GABAergic transmission⁵³ and restores impaired hippocampus-based memory tasks in a mouse model of Down syndrome⁵⁴. Thus, EE constitutes a non-invasive and non-pharmacological way for reduction of the GABAergic signalling. It remains to be determined whether the tonic and phasic GABAergic components are equally affected by EE exposure. Indeed, developmental control of corticostriatal STDP and expression of anti-Hebbian bidirectional STDP depend mainly on tonic GABAergic signalling¹⁷. In addition, in the barrel cortex, in in vivo anaesthetised rats, tLTP occurrence depends on GABAergic tone¹⁸. The temporal (Δt_STDP) shift of the occurrence of striatal tLTP on the post-pre pairing side depending on the SE/EE and/or anaesthetic regime suggests that the plasticity machinery is present but tLTP cannot be expressed. One hypothesis, in line with Gambino and Holtmaat (2012), is that GABAergic circuits are activated or inactivated depending on the Δt_STDP and environment/anaesthesia regime, thus precluding or favouring, respectively, the occurrence of tLTP. Therefore, by decreasing the inhibitory tone⁵³, EE would promote tLTP expression, whereas anaesthesia would disfavour tLTP.

The effects of EE on plasticity, and in particular on LTP, have been mainly tested ex vivo (acute brain slices) in the neocortex or the hippocampus and remain controversial⁵¹. This is probably due to the wide variety of EE conditions (for example age, sex and strain differences, amount of enrichment or duration of EE exposure) used across studies⁷. Effects of EE on hippocampal neurogenesis, neuronal morphology and synaptic plasticity vary as a function of the duration of EE and the age of initial exposure to EE⁵⁵. This is also exemplified in MSNs of the dorsal striatum, since 2–3 months of EE produced higher spine densities⁵⁶ and higher accumulation of delta-fosB⁵⁷ but no noticeable change was detected, in terms of cell volume and dendritic length, after 4–5 months of EE exposure⁵⁸. We exposed rats to EE for eight weeks after weaning, and it has been shown that this EE condition promotes LTP (with a rate-coding paradigm) and an increase in spine density in the hippocampus^21,55,59; note that six weeks EE was not sufficient to promote significant hippocampal LTP. In a mouse model of Fragile X syndrome, in which the tLTP induction threshold was increased in the prefrontal cortex, tLTP was restored to wild-type levels after exposure to EE for one month⁶⁰.

Various neuromodulators (such as dopamine, noradrenaline, acetylcholine, brain-derived neurotrophic factor (BDNF), NO, GABA) control STDP expression and polarity (for reviews see^20,61). In the striatum, dopamine is required for STDP expression in vitro^38,39,62 and in vivo^42,47,63 and has been shown to transform eligibility traces into plasticity⁶³; BDNF promotes endocannabinoid-mediated STDP⁶⁴ and GABA acts as an anti-Hebbian/Hebbian switch for STDP polarity^16,17,37. Effects of neuromodulators on STDP have been extensively investigated in the hippocampus and prefrontal cortex^2,4,51, but remain less documented in the striatum. Striatal dopamine level seems to be inert to EE or even slightly decreased⁵¹. Therefore, dopamine should not impact significantly STDP expression in SE vs EE. In the somatosensory cortex, 4–6 weeks of EE exposure induced a functional and structural plasticity by sharpening cortical whisker representation in vivo in adult rats^65,66 and resulted in BDNF increase^4,67. If a similar effect occurs in the striatum, endocannabinoid-mediated tLTD and tLTP⁶⁴ and NMDAR-mediated LTP⁶⁸ would be then favoured (because these forms of plasticity are controlled by BDNF), and less failure in STDP expression should be observed. This is in line with our observations, although additional data are required to firmly determine the STDP expression map in EE. EE, by decreasing GABAergic inhibition, as shown in the cerebral cortex⁵³, is expected to stabilize an anti-Hebbian striatal STDP, as reported in our study (Fig. 6).

Exposure to EE has been tested in rodent models of various nervous system disorders, mainly in pathology for which no pharmacological treatments are available (such as Huntington’s and Alzheimer diseases or Rett’s and Down’s syndrome), and beneficial effects have been reported^2,4. EE can also serve as a non-pharmacological treatment for cognitive enhancement^3,69,70,71. Our study shows the crucial impact of environment on in vivo plasticity at the single-cell level in an associative Hebbian synaptic plasticity such as STDP. This stresses the fact that together with in vivo recordings in awake animals (patch-clamp, two-photon or multi-channel recordings), it is crucial to perform such challenging experiments in animals subjected to EE exposure⁷. EE exposure would guarantee normal levels of plasticity compared to SE, this later would mask all the benefit derived from in vivo recordings. Although it is tempting to parallel EE exposure in rodents and the cognitive reserve theory in humans⁷², it would be essential to estimate at the single-cell level the precise change of associative memory and learning in awake and behaving animals subjected to various forms of EE.

Data availability

All experimental data are available on request.

References

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Acknowledgements

We thank the members of the LV laboratory for helpful suggestions and critical comments. TMH is a Research Fellow of University of Basque Government. This work was supported by grants from INSERM, Collège de France and CNRS. This work has been supported by grants from the Basque Country (PPGA19/15), INSERM, CNRS and College de France. T.M. was supported by a postdoctoral grant from the Basque government.

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These authors contributed equally: Teresa Morera-Herreras and Yves Gioanni.

Authors and Affiliations

Team Dynamic and Pathophysiology of Neuronal Networks, Center for Interdisciplinary Research in Biology, College de France, CNRS UMR7241/INSERM U1050, MemoLife Labex, Paris, France
Teresa Morera-Herreras, Yves Gioanni, Sylvie Perez, Gaetan Vignoud & Laurent Venance
Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940, Leioa, Bizkaia, Spain
Teresa Morera-Herreras
Neurodegenerative Diseases Group, BioCruces Bizkaia Health Research Institute, 48903, Barakaldo, Bizkaia, Spain
Teresa Morera-Herreras

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Teresa Morera-Herreras
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Yves Gioanni
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Sylvie Perez
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Gaetan Vignoud
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Laurent Venance
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Contributions

T.M.H., Y.G. and L.V. designed the study; T.M.H and Y.G. performed the in vivo experiments and analysis; G.V. performed the analysis of the in vivo experiments; S.P. performed the in vitro (brain slices) experiments and analysis; T.M.H., Y.G. and L.V. wrote the manuscript.

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Correspondence to Laurent Venance.

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Morera-Herreras, T., Gioanni, Y., Perez, S. et al. Environmental enrichment shapes striatal spike-timing-dependent plasticity in vivo. Sci Rep 9, 19451 (2019). https://doi.org/10.1038/s41598-019-55842-z

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Received: 20 June 2019
Accepted: 27 November 2019
Published: 19 December 2019
DOI: https://doi.org/10.1038/s41598-019-55842-z
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Environmental enrichment shapes striatal spike-timing-dependent plasticity in vivo

Abstract

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Introduction

Materials and Methods

Animals

Rearing environments

Standard housing environment

Enriched housing environment

In vivo single-unit intracellular recordings

Animal preparation

Deep anaesthesia experiments

Light anaesthesia experiments

In vivo intracellular (sharp pipette electrode) recordings

STDP induction protocols

Electrophysiological data analysis

Whole-cell patch-clamp recordings in acute brain slices

Brain slice preparation

Patch-clamp electrophysiological recordings

STDP induction protocols

Trichloroethanol treatment

Patch-clamp data analysis

Immunohistochemistry

Results

Properties of corticostriatal transmission in vivo

In vivo STDP in deeply anaesthetised rats grown in standard housing

Anaesthesia with chloral hydrate favours tLTD

Light anaesthesia status favours in vivo bidirectional plasticity

Environmental enrichment promotes bidirectional in vivo plasticity (centred on ΔtSTDP = −50 ms)

Environmental enrichment associated with light anaesthesia promotes bidirectional STDP (centred on ΔtSTDP = 0 ms)

Comparison of STDP in rats reared in SE or EE, and recorded in deep or light anaesthesia

Discussion

Data availability

References

Acknowledgements

Author information

Authors and Affiliations

Contributions

Corresponding author

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Competing interests

Additional information

Supplementary information

Supplementary Figures and legends

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Anti-Hebbian plasticity drives sequence learning in striatum

Electrical stimulation methods and protocols for the treatment of traumatic brain injury: a critical review of preclinical research

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Environmental enrichment promotes bidirectional in vivo plasticity (centred on Δt_STDP = −50 ms)

Environmental enrichment associated with light anaesthesia promotes bidirectional STDP (centred on Δt_STDP = 0 ms)