| Popis: |
The ability to unleash and control the brain’s often latent yet tremendous capacity for plasticity is a fundamental goal for neuroscience and medicine. If we can understand and manipulate the structures and mechanisms that constrain plasticity, then we may be able to help avert or reverse the consequences of neurodevelopmental disorders and potentially repair the brain after injury. Our broad goals are (1) to identify mechanisms that enable enhanced neural plasticity in adults, and (2) to reactivate them in a model of the neurodevelopmental disorder, Rett syndrome (RTT). RTT in humans is caused by mutations in methyl CpG binding protein 2 (MECP2). There is abundant evidence that loss of function of Mecp2 in mice interferes with activation of programs for neural plasticity in juveniles and adults. We have established the natural and ethologically-relevant behavior, maternal pup retrieval, as a sensitive assay for adult experience-dependent cortical plasticity in female Mecp2+/- mice (Mecp2het). We focused on the auditory cortex (ACtx) because it is essential for perceiving the ultrasonic cries of pups that require maternal care. First, when virgin female mice are exposed to pups, they undergo remodeling of inhibitory networks in ACtx that correlates with improved maternal behavior. Second, both Mecp2het and mice with Mecp2 deleted only in ACtx fail to learn retrieval. They also show highly altered molecular and neurophysiological features in inhibitory networks, including overexpression of parvalbumin (PV) and perineuronal nets (PNNs). Third, we devised genetic and pharmacological strategies that remediated the overexpression and restored maternal care. Finally, we demonstrated that Mecp2 mutations in parvalbumin-expressing interneurons (PVn) are critical for the early establishment of the inhibitory plasticity in the ACtx that facilitates vocal perception and maternal care. We are therefore in position to make direct links between the impairment of ongoing behavior and neuronal dynamics in freely moving animals and the underlying cellular pathology of neural plasticity in Mecp2het. Aim 1 is to manipulate ACtx inhibitory circuitry and assess the effects on behavioral and neural plasticity. We will test the hypothesis that adult plasticity can be triggered by suppression of cortical PVn. Aim 2 is to make and compare neuronal recordings from identified PVn that are Mecp2+ or Mecp2-. We hypothesize that the maturity of an individual PNN is a cell-autonomous consequence of the activity level in the PVn it surrounds. Aim 3 is to observe and manipulate noradrenergic (NA) input to ACtx during maternal experience-dependent plasticity. We will test the hypothesis that arousal-dependent ACtx activity mediated by locus coeruleus is crucial for regulating adult cortical plasticity via interaction with PVn inhibitory networks. Execution of these aims will reveal principles for regulating adult plasticity and allow us to connect them to both cellular properties and behavior. This could point the way to strategies for repairing damaged or improperly developed brain by activating latent plasticity. |
