The paraventricular thalamus controls a central amygdala fear circuit

Abstract

Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behavior. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors1-3. However, the role of PVT in the establishment of adaptive behavioral responses remains unclear. Here we show in mice that PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression4,5. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM+) CeL neurons, which has previously been shown to store fear memory6. Consistently, we found that PVT neurons preferentially innervate SOM+ neurons in the CeL, and stimulation of PVT afferents facilitated SOM+ neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression5,6. Notably, PVT modulation of SOM+ CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in PVT or Trkb in SOM+ CeL neurons impaired fear conditioning, while infusion of BDNF into CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT–CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behavior.

Forming competing fear learning and extinction memories in adolescence makes fear difficult to inhibit

“…The posterior PVT has robust projections to the CeA, BLA, and bed nucleus of the stria terminalis (Li and Kirouac 2008;Hsu et al 2014), making it well-placed to influence fear expression. The most prominent projection originating from the posterior PVT is to the lateral division of the CeA (CeL) (Li and Kirouac 2008;Vertes and Hoover 2008) and selective suppression of CeL-projecting PVT neurons impaired fear retrieval (Do-Monte et al 2015;Penzo et al 2015) and retrieval remained impaired the day after the silencing of these neurons (Do-Monte et al 2015). The PVT is necessary for CS-elicited fear when animals are tested in either the same (Padilla-Coreano et al 2012;Li et al 2014;Do-Monte et al 2015) or a different (Penzo et al 2015) context as conditioning, and PVT neurons are activated when rats are returned to a context previously associated with footshock (Beck and Fibiger 1995;Yasoshima et al 2007).…”

Fear Memory

“…CeL is the output nucleus of the amygdala (FIGURE 1A) (98,484,543,544), but it also participates in its acquisition and consolidation (345). CeM is a major regulator of fear learning via the gating of CeL cells (124,345,496). The LA and to a large extent its larger neighbor, the BLA nuclear complex, are rather input nuclei, as will be seen (98, 324,329,335,336,350,380,448,465,561).…”

“…Solid recent evidence using in part optogenetic methods has shown that the PVT innervates and regulates CeL neuronal activity, both during (496) and 7 and 24 days after cellular consolidation of fear conditioning (429), and during fear retrieval (429,496). The PVT input acts upon somatostatin-containing neurons of CeL, but not in neurons that do not contain this peptide (429).…”

“…Thus the PVT has become a very major player in fear conditioning circuitry and in fact gates CeL activity. This recent inclusion of the PVT and its connection with the CeL in learning, cellular consolidation, late consolidation, and retrieval of fear memory has changed current views on fear circuitry quite considerably (124,345,429,496). It has also changed long-standing views on the role of the midline thalamic nuclei in arousal and awareness (638a).…”

Chemogenetic Inactivation of Dorsal Anterior Cingulate Cortex Neurons Disrupts Attentional Behavior in Mouse

“…It is also possible that a functional interaction between ACC and PL neurons, associated with preparatory attention in rats, could be disrupted in the present study . Our Cre-dependent viral approach in mouse provides a template for future circuit-specific chemogenetic studies for alternative combinatorial approaches to address such possibilities; replacing AAV8-Cre with retrograde traveling Canine adenovirus type 2 (CAV)-Cre in axonal projecting areas will permit Cre expression only within unique projection circuits (Boender et al, 2014;Carter et al, 2013;Penzo et al, 2015). This chemogenetic dissection approach can serve as a powerful tool to deduce which circuits inhibited by global dACC inactivation primarily contribute to attention deficits.…”