Infusing brain-derived neurotrophic factor (BDNF) into the infralimbic (IL) prefrontal cortex is capable of inducing extinction. Little is known, however, about the circuits mediating BDNF effects on extinction or the extent to which extinction requires BDNF in IL. Using local pharmacological infusion of BDNF protein, or an antibody against BDNF, we found that BDNF in the IL, but not prelimbic (PL) prefrontal cortex, is both necessary and sufficient for fear extinction. Furthermore, we report that BDNF in IL can induce extinction of older fear memories (14 days) as well as recent fear memories (1 day). Using immunocytochemistry, we show that BDNF is increased in the ventral hippocampus (vHPC), but not IL or PL, following extinction training. Finally, we observed that infusing BDNF into the vHPC increased the firing rate of IL, but not PL neurons in fear conditioned rats. These findings indicate that an extinction-induced increase in BDNF within the vHPC enhances excitability in IL targets, thereby supporting extinction memories.
Stress exposure enhances glutamatergic signaling in the BLA-L2/3plPFC reciprocal circuit… .. 36 Endocannabinoid signaling broadly inhibits glutamatergic input from the BLA to the plPFC .... 41 Stress impairs 2-AG-mediated inhibition of the BLA-plPFC reciprocal glutamatergic circuits ..
Acquisition and extinction of learned fear responses utilize conserved but flexible neural circuits. Here we show that acquisition of conditioned freezing behavior is associated with dynamic remodeling of relative excitatory drive from the basolateral amygdala (BLA) away from corticotropin releasing factor-expressing (CRF+) central lateral amygdala (CeL) neurons, and toward non-CRF+ (CRF−) and somatostatin-expressing (SOM+) neurons, while fear extinction training remodels this circuit back toward favoring CRF+ neurons. Importantly, BLA activity is required for this experience-dependent remodeling, while directed inhibition of the BLA-CeL circuit impairs both fear memory acquisition and extinction memory retrieval. Additionally, ectopic excitation of CRF+ neurons impairs memory acquisition and facilities extinction, whereas CRF+ neuron inhibition impairs extinction memory retrieval, supporting the notion that CRF+ neurons serve to inhibit learned freezing behavior. These data suggest afferent-specific dynamic Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces the symptoms of treatment-resistant obsessive compulsive disorder (OCD), and improves response to extinction-based therapies. We recently reported that DBS-like stimulation of a rat homologue of VC/VS, the dorsal-VS, reduced conditioned fear and enhanced extinction memory (Rodriguez-Romaguera et al., 2012). In contrast, DBS of the ventral-VS had the opposite effects. To examine possible mechanisms of these effects, we assessed the effects of VS DBS on the expression of the neural activity marker Fos and brain-derived neurotrophic factor (BDNF), a key mediator of extinction plasticity in prefrontal-amygdala circuits. Consistent with decreased fear expression, DBS of dorsal-VS increased Fos expression in prelimbic and infralimbic prefrontal cortices and in the lateral division of the central nucleus of amygdala, an area that inhibits amygdala output. Consistent with improved extinction memory, we found that DBS of dorsal-VS, but not ventral-VS, increased neuronal BDNF expression in prelimbic and infralimbic prefrontal cortices. These rodent findings are consistent with the idea that clinical DBS of VC/VS may augment fear extinction through an increase in BDNF expression.
Brain-derived neurotrophic factor (BDNF) is critical for establishing activity-related neural plasticity. There is increasing interest in the mechanisms of active avoidance and its extinction, but little is known about the role of BDNF in these processes. Using the platform-mediated avoidance task combined with local infusions of an antibody against BDNF, we show that blocking BDNF in either prelimbic (PL) or infralimbic (IL) medial prefrontal cortex during extinction training impairs subsequent recall of extinction of avoidance, differing from extinction of conditioned freezing. By combining retrograde tracers with BDNF immunohistochemistry, we show that extinction of avoidance increases BDNF expression in ventral hippocampal (vHPC) neurons, but not amygdala neurons, projecting to PL and IL. Using the CRISPR/Cas9 system, we further show that reducing BDNF production in vHPC neurons impairs recall of avoidance extinction. Thus, the vHPC may mediate behavioral flexibility in avoidance by driving extinction-related plasticity via BDNFergic projections to both PL and IL. These findings add to the growing body of knowledge implicating the hippocampal-prefrontal pathway in anxiety-related disorders and extinction-based therapies.
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