Figure 3.

Neurocircuitry underlying the PTSD-like phenotype expressed by socially isolated mice. This is a simplified schematic representation of mouse brain neurocircuitry regulating emotional behavior under physiological (group-housed) and stress-induced deficits (social isolation). The prefrontal cortex and hippocampus directly project to the amygdaloid nuclei to regulate their hyperactivity following traumatic events (Herry et al., 2008). In susceptible individuals, a stressful experience is associated with impairment of cortical inhibitory activity directed to the amygdala, which results in exaggerated hyperactivity and inappropriate fear responses (Akirav and Maroun, 2007; Raber et al., 2019). In PTSD, amygdala hyperactivity is part of a maladaptive emotional processing resulting from exposure to traumatic events. The neural substrates of these behavioral deficits may result from decreased GABA release (downregulated allopregnanolone concentrations (Rasmusson et al., 2006, 2019), in participation with changes in GABA_A receptor subunit subtypes (Geuze et al., 2008). Collectively, these neurobiological alterations may explain emergence of PTSD symptoms (Pinna, 2018). In the socially isolated mice, a stress-induced model of PTSD-like behavioral traits, cortical and hippocampal projections directed to the basolateral amygdala (BLA) show a downregulation of allopregnanolone biosynthesis and behavioral correlates, including increased fear responses and impairment of fear extinction (Agís-Balboa et al., 2007; Pinna et al., 2009). In socially isolated mice (right panel), allopregnanolone downregulation in cortical and hippocampus pyramidal glutamatergic neurons and in pyramidal-like neurons of the BLA may represent the molecular underpinnings that recapitulate an increased excitability of the neuronal pathway that converges to the intercalated GABAergic neurons (ITC) and central amygdala (CeA) GABAergic spiny neurons (Agís-Balboa et al., 2007; Pinna et al., 2008). Collectively, reduction of allopregnanolone biosynthesis in corticolimbic glutamatergic neurons may impair cortico-hippocampal-amygdaloid circuits by inhibiting the GABAergic output neurons of the CeA, which project to the hypothalamus and brainstem and may explain the excessive fear responses and other behavioral deficits observed in socially isolated mice (Pinna et al., 2008, 2009). Allo, allopregnanolone; 5α-RI, 5α-reductase type I.