Activity in the Ventral Medial Prefrontal Cortex Is Necessary for the Therapeutic Effects of Extinction in Rats

Abstract

Poor response and high relapse rates remain problematic in the treatment of stress-related psychiatric disorders such as depression and post-traumatic stress disorder. Although mechanisms of pharmacotherapies are intensely studied, little is known about mechanisms of behavioral therapy that could inform improved treatments. We have previously demonstrated the therapeutic effects of extinction learning as a behavioral intervention modeling exposure therapy in rats. In the present study, we tested the hypothesis that activity in the ventral medial prefrontal cortex (vmPFC) during extinction is necessary for its therapeutic effects. The inhibitory Gi-coupled designer receptor exclusively activated by designer drug CaMKIIα-hM4Di was expressed in vmPFC before administering chronic unpredictable stress (CUS). vmPFC projection neurons were then inhibited during extinction treatment by administering clozapine--oxide. Coping behavior and cognitive flexibility were assessed 24 h later on the shock-probe defensive burying test and attentional set-shifting test, respectively. Replicating previous results, extinction reversed the CUS-induced deficits in coping behavior and cognitive flexibility. Inhibiting vmPFC during extinction blocked these therapeutic effects. Further, increasing vmPFC activity with the excitatory Gq-coupled designer receptor exclusively activated by designer drug hM3Dq 24 h before testing was sufficient to reverse the CUS-induced deficits. CUS reduced mPFC responsivity, assessed by measuring afferent-evoked field potentials in the mPFC, and this reduction was reversed by extinction treatment 24 h before testing. These results demonstrate the necessity of vmPFC activity in the therapeutic effects of extinction as a model of exposure therapy, and suggest that increased vmPFC activity induced by extinction is sufficient to produce lasting plastic changes that underlie its beneficial effects. Stress-related psychiatric disorders remain poorly treated. Psychotherapies can be effective, but their mechanisms remain unknown, hindering progress toward improved treatment. We used a rat model of behavioral therapy to identify potential targets for enhancing treatment. Fear extinction as a therapeutic behavioral intervention reversed stress-induced cognitive dysfunction and passive coping in rats, modeling components of stress-related psychiatric disease. Extinction also reversed stress-induced attenuation of mPFC responsivity. The therapeutic effects were prevented by blocking activity of glutamatergic neurons in the mPFC during extinction, and were mimicked by inducing activity in lieu of extinction. Thus, activity and plasticity in the mPFC underlie the beneficial effects of extinction on cognitive flexibility and coping behavior compromised by stress, and could be targets to enhance behavioral therapy.

Bidirectional Optogenetically-Induced Plasticity of Evoked Responses in the Rat Medial Prefrontal Cortex Can Impair or Enhance Cognitive Set-Shifting

“…However, several convergent animal studies addressing sex differences in the response to stress have indicated that females can show more resilience than males to the same chronic stress procedures, including those that cause PFC dysfunction (Luine et al, 2007;Wei et al, 2014). In the present study, a modified 21-d CUS paradigm, but not 14-d CUS, impaired performance in the mPFC-mediated set-shifting task in females comparably to the stress-induced set-shifting deficits reported in male rats after 14-d CUS (Bondi et al, 2008;Jett et al, 2017;Fucich et al, 2018). It is possible that removing social defeat stress from the female stress protocol contributed to the need for longer CUS treatment to reach the same behavioral deficit, as social defeat is one of the more robust stress procedures in the CUS protocol.…”

“…Notably, mPFC activity is normalized in patients that receive effective behavioral therapy (Yoshimura et al, 2014). Congruently, preclinical studies have demonstrated that chronic unpredictable stress (CUS) impaired cognitive flexibility and attenuated electrical responses evoked in the mPFC by stimulating the excitatory afferent from the mediodorsal thalamus (MDT; Bondi et al, 2008;Fucich et al, 2018). Further, a rat model of behavioral therapy by extinction training effectively restored the afferent-evoked mPFC response and reversed the cognitive set-shifting deficit in stressed rats (Fucich et al, 2016(Fucich et al, , 2018.…”

Shock-probe Defensive Burying Test to Measure Active versus Passive Coping Style in Response to an Aversive Stimulus in Rats

“…Originally described by Pinel and Treit in 1978, we have adopted the shock-probe defensive burying test in our lab to model central components of stress-related psychiatric illness, i.e ., preference for passive, avoidant coping strategies versus adaptive, active coping strategies. Using the protocol described here, we have shown that chronic unpredictable stress induces a shift from active to passive coping in adult Sprague-Dawley rats in this test (Jett et al ., 2015; Hatherall et al ., 2017; Fucich et al ., 2016 and 2018), modeling the maladaptive, avoidant coping strategies adopted by patients across many stress-related psychiatric illnesses (Koolhaas et al ., 1999; Bondi et al ., 2007). We have previously described the validity of this test as a measure of anxiety-like responding (see Lapiz-Bluhm et al ., 2008), and have more recently shown the efficacy of novel antidepressant drugs as well as behavioral therapy in reversing chronic stress-induced shifts in coping style choice (Jett et al ., 2015; Hatherall et al ., 2017; Fucich et al ., 2016 and 2018).…”

“…Unpublished findings from our lab suggest that surgical disruption of medial prefrontal cortex with chronic cannula implants can abolish burying behavior. Thus, when we have tested the role of this brain region in defensive burying, we have used angled approaches to target the medial prefrontal cortex while minimizing tissue damage to this region with our implants (see Fucich et al ., 2016 and 2018). …”

“…It has been well-established that rats faced with a novel object in their environment will contact it. Rats will typically make contact with the probe within 30 sec (Fucich et al ., 2018). In the rare case, the rat will not approach the probe to receive a shock within 15 min of beginning the test, discontinue testing and exclude the subject from the experiment, noting the exclusion.…”