Loss of Intercalated Cells (ITCs) in the Mouse Amygdala ofTshz1Mutants Correlates with Fear, Depression, and Social Interaction Phenotypes

Abstract

The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that is required for the proper migration and differentiation of ITCs. In the absence of, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this,-null mutants also show a loss of ITCs at postnatal time points, suggesting that may function downstream of in the maintenance of ITCs. Behavioral analysis of male cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that plays a critical role in the development of ITCs and that fear, depression-like and social behavioral deficits arise in their absence. We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the locus.

Chronic psychosocial stress during pregnancy affects maternal behavior and neuroendocrine function and modulates hypothalamic CRH and nuclear steroid receptor expression

“…The OFT was conducted on PP7, as previously described 49 . Motor activity was recorded for 1 h and data analyzed in 5-min intervals.…”

“…The EZM was conducted on PP8, as previously described 49 . Amount of time spent in the open arms was recorded over a 5-min period.…”

Midbrain dopaminergic inputs gate amygdala intercalated cell clusters by distinct and cooperative mechanisms

“…DA is also released in the amygdala during affective states such as stress (Belujon and Grace, 2015; Yokoyama et al, 2005). Therefore, it is intriguing to speculate that dopaminergic modulation of distinct ITCs clusters may also play a role in other processes such as reward learning and addiction, as well as in the control of mood-related behavior such as anxiety- and depression-like behavior (Ferrazzo et al, 2019; Kuerbitz et al, 2018).…”

Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence

“…Genetic lineage studies have shown that Gsx2-expressing LGE progenitors ultimately give rise to both neurons and glia (Kessaris et al, 2006;Fogarty et al, 2007;Qin et al, 2016). Accordingly, analysis of Gsx2 mutants revealed an essential role for Gsx2 in generating the above-mentioned LGE-derived neuronal subtypes (Toresson et al, 2000;Corbin et al, 2000;Yun et al, 2001;Waclaw et al, 2009Waclaw et al, , 2010Kuerbitz et al, 2018). Gsx2 regulates the generation of these neuronal subtypes through the upregulation of the proneural basic helix-loop-helix (bHLH) factor Ascl1 (Toresson et al, 2000;Corbin et al, 2000;Yun et al, 2001;Waclaw et al, 2009;Wang et al, 2009).…”