Single prolonged stress (SPS) has been used to examine mechanisms via which stress exposure leads to post-traumatic stress disorder symptoms. SPS induces fear extinction retention deficits, but neural circuits critical for mediating these deficits are unknown. To address this gap, we examined the effect of SPS on neural activity in brain regions critical for extinction retention (i.e., fear extinction circuit). These were the ventral hippocampus (vHipp), dorsal hippocampus (dHipp), basolateral amygdala (BLA), prelimbic cortex (PL), and infralimbic cortex (IL). SPS or control rats were fear conditioned then subjected to extinction training and testing. Subsets of rats were euthanized after extinction training, extinction testing, or immediate removal from the housing colony (baseline condition) to assay c-Fos levels (measure of neural activity) in respective brain region. SPS induced extinction retention deficits. During extinction training SPS disrupted enhanced IL neural activity and inhibited BLA neural activity. SPS also disrupted inhibited BLA and vHipp neural activity during extinction testing. Statistical analyses suggested that SPS disrupted functional connectivity within the dHipp during extinction training and increased functional connectivity between the BLA and vHipp during extinction testing. Our findings suggest that SPS induces extinction retention deficits by disrupting both excitatory and inhibitory changes in neural activity within the fear extinction circuit and inducing changes in functional connectivity within the Hipp and BLA.

Post traumatic stress disorder (PTSD) is a debilitating anxiety disorder resulting from traumatic stress exposure. Females are more likely to develop PTSD than males, but neurobiological mechanisms underlying female susceptibility are lacking. This can be addressed by using nonhuman animal models. Single prolonged stress (SPS), a nonhuman animal model of PTSD, results in cued fear extinction retention deficits and hippocampal glucocorticoid receptor (GR) upregulation in male rats. These effects appear linked in the SPS model, as well as in PTSD. However, the effects of SPS on cued fear extinction retention and hippocampal GRs in female rats remain unknown. Thus, we examined sex differences in SPS-induced cued fear extinction retention deficits and hippocampal GR upregulation. SPS induced cued fear extinction retention deficits in male rats but not female rats. SPS enhanced GR levels in the dorsal hippocampus of female rats, but not male rats. SPS had no effects on ventral hippocampal GR levels, but ventral hippocampal GR levels were attenuated in female rats relative to males. These results suggest that female rats are more resilient to the effects of SPS. The results also suggest that GR upregulation and cued fear extinction retention deficits can be dissociated in the SPS model. Keywords: sex differences, stress, post traumatic stress disorder, extinction recall, fear, glucocorticoids

Previous research has shown that the ventral medial prefrontal cortex (vmPFC) and hippocampus (Hipp) are critical for extinction memory. Basal forebrain (BF) cholinergic input to the vmPFC and Hipp is critical for neural function in these substrates, which suggests BF cholinergic neurons may be critical for extinction memory. In order to test this hypothesis, we applied cholinergic lesions to different regions of the BF and observed the effects these lesions had on extinction memory. Complete BF cholinergic lesions induced contextual fear memory generalization, and this generalized fear was resistant to extinction. Animals with complete BF cholinergic lesions could not acquire cued fear extinction. Restricted cholinergic lesions in the medial septum and vertical diagonal bands of Broca (MS/vDBB) mimicked the effects that BF cholinergic lesions had on contextual fear memory generalization and acquisition of fear extinction. Cholinergic lesions in the horizontal diagonal band of Broca and nucleus basalis (hDBB/NBM) induced a small deficit in extinction of generalized contextual fear memory with no accompanying deficits in cued fear extinction. The results of this study reveal that MS/vDBB cholinergic neurons are critical for inhibition and extinction of generalized contextual fear memory, and via this process, may be critical for acquisition of cued fear extinction. Further studies delineating neural circuits and mechanisms through which MS/vDBB cholinergic neurons facilitate these emotional memory processes are needed.

Early-life adversity is known to disrupt behavioral trajectories and many rodent models have been developed to characterize these stress-induced outcomes. One example is the scarcity-adversity model of low nesting resources. This model employs resource scarcity (i.e., low nesting materials) to elicit adverse caregiving conditions (including maltreatment) toward rodent neonates. Our lab utilizes a version of this model wherein caregiving exposures occur outside the home cage during the first postnatal week. The aim of this study was to determine adolescent and adult phenotypic outcomes associated with this model, including assessment of depressive- and anxiety-like behaviors and performance in different cognitive domains. Exposure to adverse caregiving had no effect on adolescent behavioral performance whereas exposure significantly impaired adult behavioral performance. Further, adult behavioral assays revealed substantial differences between sexes. Overall, data demonstrate the ability of repeated exposure to brief bouts of maltreatment outside the home cage in infancy to impact the development of several behavioral domains later in life.

Using the single prolonged stress (SPS) animal model of post traumatic stress disorder (PTSD), previous studies suggest that enhanced glucocorticoid receptor (GR) expression leads to cued fear extinction retention deficits. However, it is unknown how the endogenous ligand of GRs, corticosterone (CORT), may contribute to extinction retention deficits in the SPS model. Given that CORT synthesis during fear learning is critical for fear memory consolidation and SPS enhances GR expression, CORT synthesis during fear memory formation could strengthen fear memory in SPS rats by enhancing GR activation during fear learning. In turn, this could lead to cued fear extinction retention deficits. We tested the hypothesis that CORT synthesis during fear learning leads to cued fear extinction retention deficits in SPS rats by administering the CORT synthesis inhibitor metyrapone to SPS and control rats prior to fear conditioning, and observed the effect this had on extinction memory. Inhibiting CORT synthesis during fear memory formation in control rats tended to decrease cued freezing, though this effect never reached statistical significance. Contrary to our hypothesis, inhibiting CORT synthesis during fear memory formation disrupted extinction retention in SPS rats. This finding suggests that even though SPS exposure leads to cued fear extinction memory deficits, CORT synthesis during fear memory formation enhances extinction retention in SPS rats. This suggests that stress-induced CORT synthesis in previously stressed rats can be beneficial.