Effects of magnesium pemoline on the habituation of an innate fear response in Carassius auratus

The ventral hippocampus (vHPC) is critical for both learned and innate fear, but how discrete projections control different types of fear is poorly understood. Here, we report a novel excitatory circuit from a subpopulation of the ventral hippocampus CA1 subfield (vCA1) to the inhibitory peri-paraventricular nucleus of the hypothalamus (pPVN) which then routes to the periaqueductal grey (PAG). We find that vCA1→pPVN projections modulate both learned and innate fear. Fiber photometric calcium recordings reveal that activity in vCA1→pPVN projections increases during the first moments of exposure to an unconditioned threat. Chemogenetic or optogenetic silencing of vCA1→pPVN cell bodies or vCA1→pPVN axon terminals in the pPVN enhances the initial magnitude of both active and passive unconditioned defensive responses, irrespective of the sensory modalities engaged by a particular innate threat. Moreover, silencing produces a dramatic impact on learned fear without affecting milder anxiety-like behaviors. We also show that vCA1→pPVN projections monosynaptically route to the PAG, a key brain region that orchestrates the fear response. Surprisingly, optogenetic silencing of vCA1 terminals in the pPVN titrates the level of c-Fos neural activity in the PAG differently for learned versus innate threats. Together, our results show how a novel vCA1→pPVN circuit modulates neuronal activity in the PAG to regulate both learned and innate fear. These findings have implications for how initial trauma processing may influence maladaptive defensive behaviors across fear and trauma-related disorders.

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CART neuropeptide modulates the extended amygdalar CeA-vBNST circuit to gate expression of innate fear

10.1101/096610 ◽

2016 ◽

Author(s):

Abhishek Rale ◽

Ninad Shendye ◽

Devika S Bodas ◽

Nishikant Subhedar ◽

Aurnab Ghose

Keyword(s):

Conditioned Fear ◽

Stria Terminalis ◽

Fear Response ◽

Bed Nucleus ◽

Freezing Response ◽

Central Processing ◽

Panic Disorders ◽

Local Levels ◽

Innate Fear ◽

Excitatory Drive

ABSTRACTInnate fear is critical for the survival of animals and is under tight homeostatic control. Deregulation of innate fear processing is thought to underlie pathological phenotypes including, phobias and panic disorders. Although central processing of conditioned fear has been extensively studied, the circuitry and regulatory mechanisms subserving innate fear remain relatively poorly defined.In this study, we identify cocaine- and amphetamine-regulated transcript (CART) neuropeptide signaling in the central amygdala (CeA) - ventral bed nucleus of stria terminalis (vBNST) axis as a key modulator of innate fear expression. 2,4,5-trimethyl-3-thiazoline (TMT), a component of fox faeces, induces a freezing response whose intensity is regulated by the extent of CART-signaling in the CeA neurons. Abrogation of CART activity in the CeA attenuates the freezing response and reduces activation of vBNST neurons. Conversely, ectopically elevated CART signaling in the CeA potentiates the fear response concomitant with enhanced vBNST activation. We show that local levels of CART signaling modulate the activation of CeA neurons by NMDA receptor-mediated glutamatergic inputs, in turn, regulating activity in the vBNST.This study identifies the extended amygdalar CeA-vBNST circuit as a CART modulated axis encoding innate fear. CART signaling regulates the glutamatergic excitatory drive in the CeA-vBNST circuit, in turn, gating the expression of the freezing response to TMT.

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