The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants (AD), including selective serotonin reuptake inhibitors (SSRI), function by gradually improving information processing within these networks. AD have been shown to induce a state of juvenile‐like plasticity comparable to that observed during developmental critical periods: Such critical‐period‐like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals. We have coined this drug‐induced state of juvenile‐like plasticity ‘iPlasticity.’ A combination of iPlasticity induced by chronic SSRI treatment together with training, rehabilitation, or psychotherapy improves symptoms of neuropsychiatric disorders and issues underlying the developmentally or genetically malfunctioning networks. We have proposed that iPlasticity might be a critical component of AD action. We have demonstrated that iPlasticity occurs in the visual cortex, fear erasure network, extinction of aggression caused by social isolation, and spatial reversal memory in rodent models. Chronic SSRI treatment is known to promote neurogenesis and to cause dematuration of granule cells in the dentate gyrus and of interneurons, especially parvalbumin interneurons enwrapped by perineuronal nets in the prefrontal cortex, visual cortex, and amygdala. Brain‐derived neurotrophic factor (BDNF), via its receptor tropomyosin kinase receptor B, is involved in the processes of synaptic plasticity, including neurogenesis, neuronal differentiation, weight of synapses, and gene regulation of synaptic formation. BDNF can be activated by both chronic SSRI treatment and neuronal activity. Accordingly, the BDNF/tropomyosin kinase receptor B pathway is critical for iPlasticity, but further analyses will be needed to provide mechanical insight into the processes of iPlasticity.
Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.
23Critical period plasticity during early postnatal life is followed by a consolidated state through the 24 maturation of interneuron networks and development of perineuronal nets (PNN) surrounding 25 parvalbumin (PV) interneurons. However, critical period-like plasticity can be induced in the adult 26 brain (iPlasticity). Over a shorter time scale, PV interneurons can alternate between high and low 27 plasticity states (PV-plasticity) to regulate memory encoding and consolidation. 28 We now show that iPlasticity and PV-plasticity in the adult visual cortex are induced by the activation 29 of TrkB neurotrophin receptors in PV interneurons. Optical activation of TrkB specifically in PV 30 interneurons switches adult cortical networks into a state of elevated plasticity within minutes. The 31 activation changes PV properties characterized by ocular dominance plasticity and reduced PV and 32 PNN expression. Our results show that TrkB activity within PV interneurons is essential for iPlasticity 33 and orchestrates plasticity states within adult cortical networks. 34 35 36 37 38 39 40 41
Successful extinction of traumatic memories depends on neuronal plasticity in the fear extinction network. However, the mechanisms involved in the extinction process remain poorly understood. Here, we investigated the fear extinction network by using a new optogenetic technique that allows temporal and spatial control of neuronal plasticity in vivo. We optimized an optically inducible TrkB (CKII-optoTrkB), the receptor of the brain-derived neurotrophic factor, which can be activated upon blue light exposure to increase plasticity specifically in pyramidal neurons. The activation of CKII-optoTrkB facilitated the induction of LTP in Schaffer collateral-CA1 synapses after brief theta-burst stimulation and increased the expression of FosB in the pyramidal neurons of the ventral hippocampus, indicating enhanced plasticity in that brain area. We showed that optical stimulation of the CA1 region of the ventral hippocampus during fear extinction training led to an attenuated conditioned fear memory. This was a specific effect only observed when combining extinction training with CKII-optoTrkB activation, and not when using either intervention alone. Thus, TrkB activation in ventral CA1 pyramidal neurons promotes a state of neuronal plasticity that allows extinction training to guide neuronal network remodeling to overcome fear memories. Our methodology is a powerful tool to induce neuronal network remodeling in the adult brain, and can attenuate neuropsychiatric symptoms caused by malfunctioning networks.
Reproducibility is an essential feature of all scientific outcomes. Scientific evidence can only reach its true status as reliable if replicated, but the results of well-conducted replication studies face an uphill battle to be performed, and little attention and dedication have been put into publishing the results of replication attempts. Therefore, we asked a small cohort of researchers about their attempts to replicate results from other groups, as well as from their own laboratories, and their general perception of the issues concerning reproducibility in their field. We also asked how they perceive the venues, i.e. journals, to communicate and discuss the results of these attempts. To this aim we pre-registered and shared a questionnaire among scientists at diverse levels. The results indicate that, in general, replication attempts of their own protocols are quite successful (with over 80% reporting not or rarely having problems with their own protocols). Although the majority of respondents tried to replicate a study or experiment from other labs (75.4%), the median successful rate was scored at 3 (in a 1-5 scale), while the median for the general estimation of replication success in their field was found to be 5 (in a 1-10 scale). The majority of respondents (70.2%) also perceive journals as unwelcoming of replication studies.
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