Sensory loss leads to widespread cross-modal plasticity across brain areas to allow the remaining senses to guide behavior. While multimodal sensory interactions are often attributed to higher order sensory areas, cross-modal plasticity has been observed at the level of synaptic changes even across primary sensory cortices. In particular, vision loss leads to widespread circuit adaptation in the primary auditory cortex (A1) even in adults. Here we report using mice of both sexes that cross-modal plasticity occurs even earlier in the sensory processing pathway at the level of the thalamus in a modality selective manner. A week of visual deprivation reduced inhibitory synaptic transmission from the thalamic reticular nucleus (TRN) to the primary auditory thalamus (MGBv) without changes to the primary visual thalamus (dLGN). The plasticity of TRN inhibition to MGBv was observed as a reduction in postsynaptic gain and short-term depression. There was no observable plasticity of the cortical feedback excitatory...

Interstitial collateral branching of axons is a critical component in the development of functional neural circuits. Axon collateral branches are established through a series of cellular processes initiated by the development of a specialized, focal F-actin network in axons. The formation, maintenance and remodelling of this F-actin patch is critical for the initiation of axonal protrusions that are subsequently consolidated to form a collateral branch. However, the mechanisms regulating F-actin patch dynamics are poorly understood. Fmn2 is a formin family member implicated in multiple neurodevelopmental disorders. We find that Fmn2 regulates the initiation of axon collateral protrusions in chick spinal neurons and in zebrafish motor neurons. Fmn2 localises to the protrusion-initiating axonal F-actin patches and regulates the lifetime and size of these F-actin networks. The F-actin nucleation activity of Fmn2 is necessary for F-actin patch stability but not for initiating patch formation. We show that Fmn...

Many psychiatric diseases stem from an inability to cope with stressful events, as chronic stressors can precipitate or exacerbate psychopathologies. The neurobiological mechanisms underlying the response to chronic stress and the resulting anxiety states remain poorly understood. Stress neuropeptides in the extended amygdala circuitry mediate the behavioral response to stress, and hyperactivity of these systems has been hypothesized to be responsible for the emergence of persistent negative outcomes and for the pathogenesis of anxiety-related and trauma-related disorders. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1R are highly expressed within the central amygdala (CeA) and play a key role in stress regulation. Here, we used chronic social defeat stress (CSDS), a clinically relevant model of psychosocial stress that produces robust maladaptive behaviors in rodents. We found that 10 d of CSDS cause a significant increase in PACAP levels selectively in the CeA of rats, a...

Multiple recent studies have shown that motor activity greatly impacts the activity of primary sensory areas like V1. Yet, the role of this motor related activity in sensory processing is still unclear. Here, we dissect how these behavior signals are broadcast to different layers and areas of the visual cortex. To do so, we leveraged a standardized and spontaneous behavioral fidget event in passively viewing mice. Importantly, this behavior event had no relevance to any ongoing task allowing us to compare its neuronal correlates with visually relevant behaviors (e.g., running). A large two-photon Ca2+ imaging database of neuronal responses uncovered four neural response types during fidgets that were consistent in their proportion and response patterns across all visual areas and layers of the visual cortex. Indeed, the layer and area identity could not be decoded above chance level based only on neuronal recordings. In contrast to running behavior, fidget evoked neural responses that were independent to v...

Peripheral somatosensory neurons innervate the skin and sense the environment. Whereas many studies focus on initial axon outgrowth and pathfinding, how signaling pathways contribute to maintenance of the established axon arbors and terminals within the skin is largely unknown. This question is particularly relevant to the many types of neuropathies that affect mature neuronal arbors. We show that a receptor tyrosine kinase (RTK), c-Kit, contributes to maintenance, but not initial development, of cutaneous axons in the larval zebrafish before sex determination. Downregulation of Kit signaling rapidly induced retraction of established axon terminals in the skin and a reduction in axonal density. Conversely, misexpression of c-Kit ligand in the skin in larval zebrafish induced increases in local sensory axon density, suggesting an important role for Kit signaling in cutaneous axon maintenance. We found Src family kinases (SFKs) act directly downstream to mediate Kit's role in regulating cutaneous axon densit...

Principal cells in the olfactory bulb (OB), mitral and tufted cells, receive direct sensory input and generate output signals that are transmitted to downstream cortical targets. Excitatory input from glutamatergic receptor neurons are the primary known sources of rapid excitation to OB principal cells. Principal cells also receive inhibitory input from local GABAergic interneurons in both the glomerular and plexiform layers. Previous work suggests that the functional effect of these inhibitory inputs, including numerous dendrodendritic synapses with GABAergic granule cells, is to reduce firing probability. In this study, we use in vitro patch-clamp recordings to demonstrate that rat (of both sexes) OB mitral cells also can be excited by GABAergic synapses formed outside the glomerular layer. Depolarizing GABAergic responses to focal extracellular stimulation were revealed when fast ionotropic glutamate receptors were blocked, and occurred with short, monosynaptic latencies. These novel synaptic responses ...

Genetic disorders that present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis, an early-onset inherited condition caused by mutations in the Rs1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of RS1-deficient male mice, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuroglial signals as early as postnatal day 15, when eyes normally open. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Müller glia, spanning all retinal layers and disrupting light-induc...

To avoid information loss, the auditory system must adapt the broad dynamic range of natural sounds to the restricted dynamic range of auditory nerve fibers. How it solves this dynamic range problem is not fully understood. Recent electrophysiological studies showed that dynamic-range adaptation occurs at the auditory nerve level, but the amount of adaptation found was insufficient to prevent information loss. We used the physiological MATLAB Auditory Periphery model to study the contribution of efferent reflexes to dynamic range adaptation. Simulating the healthy human auditory periphery provided adaptation predictions that suggest that the acoustic reflex shifts rate-level functions toward a given context level and the medial olivocochlear reflex sharpens the response of nerve fibers around that context level. A simulator of hearing was created to decode model-predicted firing of the auditory nerve back into an acoustic signal, for use in psychophysical tasks. Speech reception thresholds in noise obtaine...

Memory for events from the distant past relies on multiple brain regions, but little is known about the underlying neural dynamics that give rise to such abilities. We recorded neural activity in the hippocampus and retrosplenial cortex of two female rhesus macaques as they visually selected targets in year-old and newly acquired object-scene associations. Whereas hippocampal activity was unchanging with memory age, the retrosplenial cortex responded with greater magnitude alpha oscillation (10–15 Hz) and greater phase locking to memory-guided eye movements during retrieval of old events. A similar old-memory enhancement was observed in the anterior cingulate cortex but in a beta2/gamma band (28–35 Hz). In contrast, remote retrieval was associated with decreased gamma-band synchrony between the hippocampus and each neocortical area. The increasing retrosplenial alpha oscillation and decreasing hippocampocortical synchrony with memory age may signify a shift in frank memory allocation or, alternatively, cha...

Persistent firing is commonly reported in both cortical and subcortical neurons under a variety of behavioral conditions. Yet the mechanisms responsible for persistent activity are only partially resolved with support for both intrinsic and synaptic circuit-based mechanisms. Little also is known about physiological factors that enable epochs of persistent firing to continue beyond brief pauses and then to spontaneously terminate. In the present study, we used intracellular recordings in rat (both sexes) neocortical and hippocampal brain slices to assess the ionic mechanisms underlying persistent firing dynamics. Previously we showed that blockade of Ether-á-go-go-Related Gene (ERG) potassium channels abolished intrinsic persistent firing in the presence of low concentrations of muscarinic receptor agonists and following optogenetic activation of cholingeric axons. Here we show the slow dynamics of ERG conductance changes allows persistent firing to outlast the triggering stimulus and even initiate discharg...