Neuromodulation of Hippocampal Cells and Circuits

Abstract

The hippocampus is a major brain centre for information processing, where subcortical neuromodulatory circuits interface with intrinsic learning circuits to assign salience to sensory information relevant to behavioural state. Glutamatergic principal cells (PCs) of the dentate gyrus (DG), CA3 and CA1 regions comprise the classic trisynaptic circuit, which compare patterns of incoming sensory stimuli with internal representations, enabling the detection of novelty. Within the trisynaptic circuitry, distinct feedforward and feedback inhibitory circuits spatiotemporally constrain the timing of PC excitability, which, together with disinhibitory circuits, synchronize PC ensembles to generate network rhythms. Neuromodulation alters network rhythms and synaptic plasticity by releasing neurotransmitters and neuropeptides onto diverse receptor subtypes, often expressed in a cell type- and circuit-specific manner. Moreover, extrinsic neuromodulation can induce the secondary release of intrinsic neuromodulators. For each neurotransmitter system, we review the structural organization and target specificity of afferent innervation, receptor subtype distribution and, where known, their functional effects on hippocampal cells and circuits. Despite the complexity involved and evident gaps in scientific knowledge, general principles of neuromodulation are emerging. With the development of next-generation technologies, the vision of understanding how neuromodulatory mechanisms engage circuit elements to regulate hippocampal memory encoding and recall is coming into sharper focus.