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Abstract
Psychiatric disorders, such as major depressive disorder and posttraumatic disorder are complex, debilitating illnesses that are difficult to treat. Current treatments are ineffective for a large portion of patients, thus understanding the neurobiological mechanisms intrinsic to these disorders is vital for their treatment. Stress-related psychiatric disorders share a common dysfunction in the medial prefrontal cortex, a brain region involved in mediating higher order executive functions, such as cognitive flexibility. Cognitive behavioral therapies, such as prolonged exposure therapy, can be effective in some treatment- resistant patients and can address medial prefrontal cortex dysfunction. Fear extinction in rodents bears similarities to exposure therapy in humans, an evidence-based treatment for fear based disorders. We have demonstrated that fear extinction reverses stress-induced deficits on cognitive flexibility and stress-induced hyporresponsivity in the medial prefrontal cortex. In addition, we have observed that extinction requires infralimbic (IL) cortical activity and de novo protein synthesis to exert these effects. However, the molecular and circuit mechanisms underlying the beneficial effects of extinction remain unknown. We tested the hypotheses that 1) extinction requires Brain Derived Neurotrophic Factor (BDNF) signaling in the IL to exert these effects, and 2) ventral hippocampal input to the IL during extinction is the likely source of BDNF-induced plasticity. Moreover, we explored whether adjunct treatment with a subtherapeutic dose of ketamine could enhance the effects of subtherapeutic extinction.
We used chronic unpredictable stress to induce deficits on set shifting performance, a form of cognitive flexibility mediated by the medial prefrontal cortex. We tested the necessity of BDNF signaling during extinction via local microinjections of a neutralizing BDNF antibody into the IL, and the rats were tested on set shifting performance 24 hours later. To test the role of the ventral hippocampal input for the effects of extinction on set shifting, we used Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs). To test the sufficiency of ventral hippocampal input to the IL to reverse stress-induced cognitive deficits, we used Gq-coupled designer receptors exclusively activated by designer drugs. We found that ventral hippocampal input to the IL is necessary for the effects of extinction, and activating this input to the IL in lieu of extinction also reverses the effects of stress.
To test adjunct treatment, we first found that reducing tone exposures during extinction (from 16 to 8 tones) produces partial effects in reversing stress-induced hyporesponsivity to afferent stimulation from the medial dorsal thalamus. Further, 8 tone extinction alone did not reverse stress-induced deficits on set shifting. A dose-response study revealed that ketamine at a dose of 1mg/kg also produced partial effects in reversing stress-induced hyporesponsivity to afferent stimulation from the medial dorsal thalamus, while also not reversing stress-induced behavioral deficits. We found that combining 1mg/kg of ketamine with 8 tone extinction completely reversed stress-induced deficits on set shifting, thus validating our use of a subtherapeutic model of extinction to study adjunct treatments. This work provides scientists and clinicians alike the opportunity to consider adjunct pharmacotherapeutic interventions that may potentially enhance the efficacy of behavioral therapy.
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