Activation of TrkB in Parvalbumin interneurons is required for the promotion of reversal learning in spatial and fear memory by antidepressants

Abstract

Critical period-like plasticity (iPlasticity) can be reinstated in the adult brain by several interventions, including drugs and optogenetic modifications. We have demonstrated that a combination of iPlasticity with optimal training improves behaviors related to neuropsychiatric disorders. In this context, the activation of TrkB, a receptor for BDNF, in Parvalbumin-positive (PV+) interneurons has a pivotal role in cortical network changes. However, it is unknown if the activation of TrkB in PV+ interneurons is important for other plasticity-related behaviors, especially for learning and memory. Here, using mice with heterozygous conditional TrkB deletion in PV+ interneurons (PV-TrkB hCKO) in IntelliCage and fear erasure paradigms, we show that chronic treatment with fluoxetine, a widely prescribed antidepressant drug that is known to promote the activation of TrkB, enhances behavioral flexibility in spatial and fear memory, largely depending on the expression of the TrkB receptor in PV+ interneurons. In addition, hippocampal long-term potentiation was enhanced by chronic treatment with fluoxetine in wild-type mice, but not in PV-TrkB hCKO mice. Transcriptomic analysis of PV+ interneurons after fluoxetine treatment indicated intrinsic changes in synaptic formation and downregulation of enzymes involved in perineuronal net formation. Consistently, immunohistochemistry has shown that the fluoxetine treatment alters PV expression and reduces PNNs in PV+ interneurons, and here we show that TrkB expression in PV+ interneurons is required for these effects. Together, our results provide molecular and network mechanisms for the induction of critical period-like plasticity in adulthood.

Hydroxytyrosol Alleviates Obesity-Induced Cognitive Decline by Modulating the Expression Levels of Brain-Derived Neurotrophic Factors and Inflammatory Factors in Mice

“…Neurons in the CNS, especially in the hypothalamus, play an important role in controlling energy balance . The hypothalamus is a key region for regulating animal feeding and energy balance, and BDNF and TrkB genes are expressed in various regions of the hypothalamus. , The BDNF signal of astrocytes regulates neuronal activity in the ventromedial hypothalamus in response to changes in energy state, and loss of BDNF signaling in the paraventricular hypothalamus leads to increased appetite, decreased motor activity, and severe obesity . In general, BDNF mainly controls weight and energy homeostasis through the hypothalamic pathway, thus indirectly affecting cognitive function .…”

Perineuronal Net Microscopy: From Brain Pathology to Artificial Intelligence

“…The selective serotonin re-uptake inhibitor and antidepressant fluoxetine causes a reduction in the PNN coating on the PFC interneurons [121]. Transcriptomics analysis in PV+ interneurons indicates that fluoxetine down-regulates enzymes involved in PNN formation and affects expression of the BDNF/TrkB signaling pathway components [123]. Notably, BDNF, NT-3, GDNF, HB-GAM (pleiotrophin), FGF, VEGF and some other neurotrophic factors have positively charged sites that bind CSPGs with high affinity (please see [14] for references).…”