Infralimbic BDNF signaling is necessary for the beneficial effects of extinction on set shifting in stressed rats

Abstract

Current pharmacotherapies for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are ineffective for many patients, and often do not restore cognitive dysfunction associated with these disorders. Behavioral therapies, such as exposure therapy, can be effective for treatment-resistant patients. The mechanisms underlying exposure therapy are not well-understood. Fear extinction as an intervention after chronic stress can model the beneficial effects of exposure therapy in rats. Extinction requires neuronal activity and protein synthesis in the infralimbic (IL) cortex for its beneficial effects. We hypothesized that extinction requires Brain-Derived Neurotrophic Factor (BDNF) activity in the IL cortex to reverse stress-induced cognitive flexibility impairments. Extinction learning reversed set-shifting deficits induced by Chronic Unpredictable Stress (CUS), tested 24 h after extinction. Blocking BDNF signaling in the IL cortex during extinction by local administration of a neutralizing antibody prevented the beneficial effects of extinction on set shifting after stress. Extinction induced activation of the BDNF TrkB receptor, and signaling pathways associated with BDNF (Akt and Erk). Administration of exogenous BDNF into IL cortex in the absence of extinction was sufficient to reverse the effects of stress on set shifting. The effects of extinction were prevented by blocking either Erk or Akt signaling in the IL cortex, whereas the effects of exogenous BDNF were dependent on Erk, but not Akt, signaling. Our observations suggest that BDNF-Erk signaling induced by extinction underlies plastic changes that can reverse or counteract the effects of chronic stress in the IL cortex.

Adjunct treatment with ketamine enhances the therapeutic effects of extinction learning after chronic unpredictable stress

“…A different acute stressor was applied each day (14 days for males, 21 days for females), including the following: 30 min restraint, 1 h shake, 24 h wet bedding, 15 min footshock, 10 min tail pinch, 15 min warm swim, 10 min cold swim, overnight lights-on. We have reported previously that 14 days of CUS does not induce set shifting deficits in females, but 21-day CUS induces a deficit in females comparable to that observed in males after 14 days CUS ( Paredes et al, 2022 ; Bulin et al, 2020 ).…”

“…41 rats (17 males, 4–5/group; 24 females, 5–7/group) were used in 4 groups (CUS-tone control + saline, CUS-Ext 8 + saline, CUS-tone control + 1.0 mg/kg ketamine, CUS-Ext 8 + 1.0 mg/kg ketamine). Ketamine was administered immediately upon completion of the extinction session to avoid confounding behavioral effects of having drug on board during extinction (some ataxia was noted, even at 1 mg/kg), and to coincide with the activation of the BDNF receptor TrkB after extinction ( Paredes et al, 2022 ).…”

“…Ketamine may enhance FE efficacy through converging mechanisms, as ketamine and FE share molecular processes in the mPFC necessary for their effects. Therapeutic effects of both ketamine and FE involve PI3 kinase-Akt signaling in the mPFC, ( Duman et al, 2012 ; Paredes et al, 2022 ; Li et al, 2010 ). FE requires infralimbic (IL) glutamatergic activity and activity-dependent protein translation in the mPFC to reverse stress-induced cognitive deficits ( Fucich et al, 2016 , 2018 ).…”

“…FE and ketamine restore stress-induced dysregulation of mPFC activity ( Fucich et al, 2018 ; Etkin and Wager, 2007 ; Helpman et al, 2016 ; Yang et al, 2018 ; Jett et al, 2015 ). Both FE and ketamine require Brain Derived Neurotrophic Factor (BDNF) signaling and activity-dependent protein translation for their effects, and require plasticity in the ventral hippocampus (vHipp)-to-mPFC pathway ( Paredes et al, 2022 ; Autry et al, 2011 ; Peters et al, 2010 ). Like FE, a single dose of ketamine (10 mg/kg) can reverse deficits induced by chronic unpredictable stress (CUS) on set shifting and active coping, and promote dendritic spine growth after stress ( Jett et al, 2015 ; Moench et al, 2016 ; Zhang et al, 2019 ).…”

Retinoic acid-gated BDNF synthesis in neuronal dendrites drives presynaptic homeostatic plasticity

“…BDNF has diverse roles in synapse function and plasticity and is implicated in the pathophysiology of various brain disorders [33][34][35][36][37]. As one of the key trans-synaptic signaling molecules, the transcription, synthesis, and secretion of BDNF are highly activity-dependent [38][39][40][41][42].…”