Nicotine modulates contextual fear extinction through changes in ventral hippocampal GABAergic function.

Numerous studies have attributed the psychopathology of anxiety and stress disorders to maladaptive behavioral responses such as an inability to extinguish fear. Therefore, understanding neural substrates of fear extinction is imperative for developing more effective therapies for anxiety and stress disorders. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs in the fear extinction process. In the present study, we first examined the involvement of several brain regions essential for fear extinction (i.e., dorsal and ventral hippocampus, dHPC and vHPC; infralimbic, IL, and prelimbic, PL of the medial prefrontal cortex, mPFC; basolateral nucleus of the amygdala, BLA) in the impairing effects of a nAChR agonist, nicotine, on contextual fear extinction in mice. Our results showed that systemic administration of nicotine during contextual fear extinction increased c-fos expression in the vHPC and BLA while not affecting dHPC, IL or PL. In line with these results, local nicotine infusions into the vHPC, but not dHPC, resulted in impaired contextual fear extinction. Interestingly, we found that local nicotine infusions into the PL also resulted in impairment of contextual fear extinction. Second, we measured the protein levels of the GABA synthesizing enzymes GAD65 and GAD67 in the dHPC and vHPC during contextual fear extinction. Our results showed that in the group that received acute nicotine, both GAD65 and GAD67 protein levels were downregulated in the vHPC, but not in dHPC. This effect was negatively correlated with the level of freezing response during fear extinction suggesting that the downregulated GAD65/67 levels were associated with disrupted fear extinction. Finally, using c-fos/GAD65/67 double immunofluorescence, we showed that nicotine mainly increased c-fos expression in non-GABAergic ventral hippocampal cells, indicating that acute nicotine increases vHPC excitability. Overall, our results suggest that acute nicotine's impairing effects on fear extinction are associated with ventral hippocampal disinhibition. Therefore, these results further our understanding of the interaction between nicotine addiction and anxiety and stress disorders by describing novel neural mechanisms mediating fear extinction.

Kutlu MG ，Connor DA ，Tumolo JM ，Cann C ，Garrett B ，Gould TJ ... -  《-》

Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear.

Sierra-Mercado D ，Padilla-Coreano N ，Quirk GJ 《-》

Acute nicotine enhances spontaneous recovery of contextual fear and changes c-fos early gene expression in infralimbic cortex, hippocampus, and amygdala.

Exposure therapy, which focuses on extinguishing fear-triggering cues and contexts, is widely used to treat post-traumatic stress disorder (PTSD). Yet, PTSD patients who received successful exposure therapy are vulnerable to relapse of fear response after a period of time, a phenomenon known as spontaneous recovery (SR). Increasing evidence suggests ventral hippocampus, basolateral amygdala, and infralimbic cortex may be involved in SR. PTSD patients also show high rates of comorbidity with nicotine dependence. While the comorbidity between smoking and PTSD might suggest nicotine may alter SR, the effects of nicotine on SR of contextual fear are unknown. In the present study, we tested the effects of acute nicotine administration on SR of extinguished contextual fear memories and c-fos immediate early gene immunohistochemistry in mice. Our results demonstrated that acute nicotine enhanced SR of extinguished fear whereas acute nicotine did not affect retrieval of unextinguished contextual memories. This suggests that the effect of acute nicotine on SR is specific for memories that have undergone extinction treatment. C-fos immunoreactive (IR) cells in the ventral hippocampus and basolateral amygdala were increased in the nicotine-treated mice following testing for SR, whereas the number of IR cells in the infralimbic cortex was decreased in the same group. Overall, this study suggests that nicotine may adversely affect context-specific relapse of fear memories and this effect is potentially mediated by the suppression of cortical regions and increased activity in the ventral hippocampus and amygdala.

Kutlu MG ，Tumolo JM ，Holliday E ，Garrett B ，Gould TJ ... -  《-》

Medial prefrontal and ventral hippocampal contributions to incidental context learning and memory in adolescent rats.

The Context Preexposure Facilitation Effect (CPFE) is a contextual fear conditioning (CFC) paradigm in which context learning, context-shock learning, and retrieval of contextual fear occur in three distinct phases. The medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC), and ventral hippocampus (vHPC) are required for the acquisition and/or consolidation of a context representation during incidental context exposure (Heroux et al., 2017; Robinson-Drummer et al., 2016; Rudy & Matus-Amat, 2006). This exposure also induces the expression of the immediate early genes (IEGs) c-Fos, Arc, Egr-1, and Npas4 in these regions (Heroux et al., 2018, 2019). Despite these studies, it is still unclear how mPFC and vHPC contribute to incidental context learning and memory. The current study examined whether prefrontal or ventral hippocampal inactivation during context preexposure interferes with long-term context memory and IEG activity in the mPFC, vHPC, dHPC and the ventral midline thalamus (VMT, a region connected to both the mPFC and HPC). Adolescent Long-Evans rats were given intra-mPFC (Experiment 1) or intra-vHPC (Experiment 2) infusions of the GABAA receptor agonist muscimol or PBS prior to context preexposure, and then were sacrificed 30 min later and whole mPFC, dHPC, vHPC, and VMT were collected and assayed for IEG mRNA expression via qPCR. Prefrontal or ventral hippocampal inactivation during context exposure abolished subsequent post-shock and retention test freezing in behaviorally-tested littermates of the sacrificed groups. In Experiment 1, prefrontal inactivation reduced expression of c-Fos, Arc, Egr-1, and Npas4 in the mPFC, c-Fos, Arc, and Npas4 in the vHPC, and c-Fos in the VMT, to the level of behaviorally-naïve home-cage controls. Prefrontal inactivation did not alter IEG expression in the dHPC during context exposure. In Experiment 2, ventral hippocampal inactivation impaired expression of all IEGs in the mPFC, dHPC, and vHPC, with no effect in the VMT. Taken together, these results suggest that context memory processes on the preexposure day of the CPFE may depend on mPFC-vHPC circuitry not typically emphasized in studies of incidental or configural learning and memory.

Heroux NA ，Horgan CJ ，Pinizzotto CC ，Rosen JB ，Stanton ME ... -  《-》

Oxytocin in dorsal hippocampus facilitates auditory fear memory extinction in rats.

Fear extinction is impaired in some psychiatric disorders. Any treatment that facilitates the extinction of fear is a way to advance the treatment of related psychiatric disorders. Recent studies have highlighted the role of oxytocin (OT) in fear extinction, but the endogenous release of OT during fear extinction in the dorsal hippocampal (dHPC) is not clear. We investigated the release of OT during fear extinction and the role of the HPC - medial prefrontal cortex (mPFC) circuit and BDNF in the effects of exogenous OT on auditory fear conditioning in male rats. We found that the release of endogenous OT in the dHPC is significantly increased during the fear extinction process as measured by the microdialysis method. Increased freezing response in the OT-treated rats compared to saline-treated rats showed that exogenous OT in the dHPC enhanced the fear extinction. Injection of BDNF antagonist (ANA-12) into the infralimbic (IL) blocked the effect of exogenous OT on the dHPC. Following OT injection, BDNF levels increased in the dHPC, ventral HPC, and IL cortex; but decreased in the prelimbic cortex (PL). Finally, OT microinjected into the dHPC significantly increased neural activity of pyramidal neurons of the CA1-vHPC and IL but decreased the neural activity in the PL cortex. Our findings strongly support that the dHPC endogenous OT plays a crucial role in enhancing fear extinction. It seems that the activation of the HPC-mPFC pathway, and consequently, the release of BDNF in the IL cortex mediates the enhancing effects of OT on fear extinction.

Bazaz A ，Ghanbari A ，Vafaei AA ，Khaleghian A ，Rashidy-Pour A ... -  《-》