Brain derived neurotrophic factor (BDNF), a neurotrophin essential for nervous system development and synaptic plasticity, has been found to have a significant influence on affective behaviors. The ...notion that an impairment in BDNF signaling might be involved in affective disorders is originated primarily from the opposing effects of antidepressants and stress on BDNF signaling. Antidepressants enhance BDNF signaling and synaptic plasticity. On the other hand, negative environmental factors such as severe stress suppress BDNF signaling, impair synaptic activity and increase susceptibility to affective disorders. Postmortem studies provided strong support for decreased BDNF signaling in depressive disorders. Remarkably, studies in humans with a single nucleotide polymorphism in the BDNF gene, the BDNF Val66Met which affects regulated release of BDNF, showed profound deficits in hippocampal and prefrontal cortical (PFC) plasticity and cognitive behaviors. BDNF regulates synaptic mechanisms responsible for various cognitive processes including attenuation of aversive memories, a key process in the regulation of affective behaviors. The unique role of BDNF in cognitive and affective behaviors suggests that cognitive deficits due to altered BDNF signaling might underlie affective disorders. Understanding how BDNF modulates synapses in neural circuits relevant to affective behaviors, particularly the medial prefrontal cortical (mPFC)–hippocampus–amygdala pathway, and its interaction with development, sex, and environmental risk factors might shed light on potential therapeutic targets for affective disorders.
This article is part of the Special Issue entitled ‘BDNF Regulation of Synaptic Structure, Function, and Plasticity’.
•BDNF influences affective behaviors by modifying neurogenesis and synapses.•Altered synaptic plasticity due to reduced BDNF might cause affective disorders.•Enhancement of cortical BDNF signaling might improve affective symptoms.
J. Neurochem. (2011) 119, 324–331.
Both oxytocin and oxytocin receptors are implicated in neuropsychiatric disorders, particularly autism which involves a severe deficit in social cognition. ...Consistently, oxytocin enhances social cognition in humans and animals. The infralimbic medial prefrontal cortex (IL‐mPFC) is believed to play an important role in the regulation of social cognition which might involve top‐down control of subcortical structures including the amygdala. However, little is known about whether and how oxytocin modulates synaptic function in the IL‐mPFC. The effect of oxytocin on excitatory neurotransmission in the IL‐mPFC was studied by examining both the evoked and spontaneous excitatory neurotransmission in the IL‐mPFC layer V pyramidal neurons before and after perfusion with oxytocin. To investigate the effect of oxytocin on synaptic plasticity, low‐frequency stimulation‐induced long‐lasting depression was studied in oxytocin‐treated brain slices. Oxytocin produced a significant suppression of glutamatergic neurotransmission in the IL‐mPFC layer V pyramidal neurons which was mediated by a reduction in glutamate release. Activation of the cannabinoid CB1 receptors was involved in this pre‐synaptic effect. Treatment of brain slices with oxytocin for 1 h converted long‐lasting depression into long‐lasting potentiation of glutamatergic neurotransmission. This oxytocin‐mediated plasticity was NMDA receptor‐dependent and was mediated by the synaptic insertion of calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors. The aforementioned suppression of basal glutamatergic neurotransmission and facilitation of activity‐dependent synaptic plasticity in the IL‐mPFC might be critical for the effect of oxytocin on social cognition.
Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. ...However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.
Recent studies suggest that low endogenous estradiol might be a susceptibility factor for anxiety and trauma-related disorders in women. Consistently, fear extinction, a form of inhibitory learning ...critical for the management of anxiety symptoms, is positively correlated with endogenous estradiol levels. To understand the synaptic basis of the effect of endogenous estradiol on fear extinction, we studied glutamatergic transmission and plasticity in the infralimbic medial prefrontal cortex (IL-mPFC), a brain region crucial for the regulation of fear extinction. Diestrus mice (low estradiol) exhibited a higher basal glutamatergic transmission compared with proestrus mice (high estradiol). Synaptic plasticity was also regulated by endogenous estradiol, which favored synaptic potentiation in a GluN2B-dependent manner. Activation of estrogen receptor β (ERβ) but not ERα rescued synaptic potentiation in diestrus mice by enhancing GluN2B-mediated NMDA receptor transmission. Our results suggest that both endogenous estradiol and ERβ activation facilitate the ability of the IL-mPFC synapses to undergo potentiation, a mechanism necessary for the regulation of fear extinction.
Fear extinction, an inhibitory learning that suppresses a previously learned fear memory, is diminished during adolescence. Earlier studies have shown that this suppressed fear extinction during ...adolescence involves an altered glutamatergic plasticity in infralimbic medial prefrontal cortical (IL-mPFC) pyramidal neurons. However, it is unclear whether the excitability of IL-mPFC pyramidal neurons plays a role in this development-dependent suppression of fear extinction. Therefore, we examined whether fear conditioning and extinction affect the active and passive membrane properties of IL-mPFC layer 5 pyramidal neurons in preadolescent, adolescent and adult mice. Both preadolescent and adult mice exhibited a bidirectional modulation of the excitability of IL-mPFC layer 5 pyramidal neurons following fear conditioning and extinction, i.e., fear conditioning reduced membrane excitability, whereas fear extinction reversed this effect. However, the fear conditioning-induced suppression of excitability was not reversed in adolescent mice following fear extinction training. Neither fear conditioning nor extinction affected GABAergic transmission in IL-mPFC layer 5 pyramidal neurons, suggesting that GABAergic transmission did not play a role in experience-dependent modulation of neuronal excitability. Our results suggest that the extinction-specific modulation of excitability is impaired during adolescence.
Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and ...function, however, remain unclear. To address this question, we generated CX3CR1CreER mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1CreER to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling.
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•CX3CR1CreER mice allow for the specific manipulation of microglial function•Microglia are important for learning and learning-dependent synaptic remodeling•Microglial BDNF is an important regulator of synaptic plasticity and function
Mice lacking microglia show defects in multiple learning tasks, with microglia-derived brain-derived neurotrophic factor being a critical factor for learning-dependent synaptic plasticity.
Accumulating evidence has shown that repeated exposure to general anesthesia during critical stages of brain development results in long-lasting behavioral deficits later in life. To date, there has ...been no effective treatment to mitigate the neurotoxic effects of anesthesia on brain development. By performing calcium imaging in the mouse motor cortex, we show that ketamine anesthesia causes a marked and prolonged reduction in neuronal activity during the period of post-anesthesia recovery. Administration of the AMPAkine drug CX546 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine to potentiate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor activity during emergence from anesthesia in mice enhances neuronal activity and prevents long-term motor learning deficits induced by repeated neonatal anesthesia. In addition, we show that CX546 administration also ameliorates various synaptic deficits induced by anesthesia, including reductions in synaptic expression of NMDA (N-methyl-d-aspartate) and AMPA receptor subunits, motor training-evoked neuronal activity, and dendritic spine remodeling associated with motor learning. Together, our results indicate that pharmacologically enhancing neuronal activity during the post-anesthesia recovery period could effectively reduce the adverse effects of early-life anesthesia.
The medial habenula-interpeduncular nucleus (MHb-IPN) pathway has recently been implicated in the suppression of fear memory. A notable feature of this pathway is the corelease of neurotransmitters ...and neuropeptides from MHb neurons. Our studies in mice reveal that an activation of substance P-positive dorsomedial habenula (dMHb) neurons results in simultaneous release of glutamate and glycine in the lateral interpeduncular nucleus (LIPN). This glycine receptor activity inhibits an activity-dependent long-lasting potentiation of glutamatergic synapses in LIPN neurons, while substance P enhances this plasticity. An endocannabinoid CB1 receptor-mediated suppression of GABA
receptor activity allows substance P to induce a long-lasting increase in glutamate release in LIPN neurons. Consistent with the substance P-dependent synaptic potentiation in the LIPN, the NK1R in the IPN is involved in fear extinction but not fear conditioning. Thus, our study describes a novel plasticity mechanism in the LIPN and a region-specific role of substance P in fear extinction.
Fear can be highly adaptive in promoting survival, yet it can also be detrimental when it persists long after a threat has passed. Flexibility of the fear response may be most advantageous during ...adolescence when animals are prone to explore novel, potentially threatening environments. Two opposing adolescent fear-related behaviours-diminished extinction of cued fear and suppressed expression of contextual fear-may serve this purpose, but the neural basis underlying these changes is unknown. Using microprisms to image prefrontal cortical spine maturation across development, we identify dynamic BLA-hippocampal-mPFC circuit reorganization associated with these behavioural shifts. Exploiting this sensitive period of neural development, we modified existing behavioural interventions in an age-specific manner to attenuate adolescent fear memories persistently into adulthood. These findings identify novel strategies that leverage dynamic neurodevelopmental changes during adolescence with the potential to extinguish pathological fears implicated in anxiety and stress-related disorders.
The only evidence-based behavioral treatment for anxiety and stress-related disorders involves desensitization techniques that rely on principles of extinction learning. However, 40% of patients do ...not respond to this treatment. Efforts have focused on individual differences in treatment response, but have not examined when, during development, such treatments may be most effective. We examined fear-extinction learning across development in mice and humans. Parallel behavioral studies revealed attenuated extinction learning during adolescence. Probing neural circuitry in mice revealed altered synaptic plasticity of prefrontal cortical regions implicated in suppression of fear responses across development. The results suggest a lack of synaptic plasticity in the prefrontal regions, during adolescence, is associated with blunted regulation of fear extinction. These findings provide insight into optimizing treatment outcomes for when, during development, exposure therapies may be most effective.
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