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Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis

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Abstract

Central regulation of hypothalamo-pituitary-adrenocortical (HPA) axis stress responses is mediated by a relatively circumscribed group of projections to the paraventricular hypothalamus (PVN). The dorsomedial hypothalamus (DMH), medial preoptic area (mPOA), and bed nucleus of the stria terminalis (BST) provide direct, predominantly inhibitory, innervation of the PVN. These PVN-projecting neurons are controlled by descending information from limbic forebrain structures, including the prefrontal cortex, amygdala, hippocampus, and septum. The neurochemical phenotype of limbic circuits targeting PVN relays has not been systematically analyzed. The current study combined retrograde tracing and immunohistochemistry/in situ hybridization to identify the specific sites of glutamatergic and GABAergic inputs to the DMH, mPOA, and BST. Following Fluoro-gold (FG) injections in the DMH, retrogradely labeled cells co-localized with vesicular glutamate transporter mRNA in the prefrontal cortex, ventral hippocampus, and paraventricular thalamus. Co-localization of FG and glutamic acid decarboxylase mRNA was present throughout the central and medial amygdaloid nuclei and septal area. In addition, the mPOA received predominantly GABAergic input from the septum, amygdala, and BST. The BST received glutamatergic projections from the hippocampus and basomedial amygdala, whereas, GABAergic inputs arose from central and medial amygdaloid nuclei. Thus, discrete sets of neurons in the hypothalamus and BST are positioned to summate limbic inputs into PVN regulation and may play a role in HPA dysfunction and stress-related illness.

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Abbreviations

AHN:

Anterior hypothalamic nucleus

BMA:

Basomedial amygdala

BST:

Bed nucleus of the stria terminalis

CeA:

Central nucleus of the amygdala

CoA:

Cortical amygdala

CRH:

Corticotrophin-releasing hormone

DMH:

Dorsomedial hypothalamus

FG:

Fluoro-gold

GAD65:

Glutamic acid decarboxylase 65

HPA:

Hypothalamo-pituitary-adrenal

LH:

Lateral hypothalamus

LS:

Lateral septum

MeA:

Medial nucleus of the amygdala

mPFC:

Medial prefrontal cortex

MPN:

Medial preoptic nucleus

NAc:

Nucleus accumbens

PA:

Posterior amygdala

PAG:

Periaqueductal gray

PH:

Posterior hypothalamus

POA:

Preoptic area

PVN:

Paraventricular nucleus of the hypothalamus

PVT:

Paraventricular nucleus of the thalamus

Reu:

Reuniens nucleus

vGluT1:

Vesicular glutamate transporter 1

vGluT2:

Vesicular glutamate transporter 2

VMH:

Ventromedial hypothalamus

vSub:

Ventral subiculum

ZI:

Zona incerta

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Acknowledgments

This work was supported by NIH grants MH049698, MH069725, MH069860, and MH090574 to JPH. The authors wish to thank Chun Xiao and Dana Ziegler for technical assistance.

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Correspondence to Brent Myers.

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Myers, B., Mark Dolgas, C., Kasckow, J. et al. Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis. Brain Struct Funct 219, 1287–1303 (2014). https://doi.org/10.1007/s00429-013-0566-y

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