Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen α3 VI (COL6A3) C-terminal domain (CTD). These Col6a3 CTT mice showed a recessive dystonia-like phenotype in both sexes. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3 CTT mice of both sexes have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid (eCB) signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3 CTT mice of both sexes was improved by CB1R agonist treatment. Our fi...

In sensory cortices, the information flow has been thought to be processed vertically across cortical layers, with layer 4 being the major thalamo-recipient which relays thalamic signals to layer 2/3, which in turn transmits thalamic information to layer 5 and 6 to then leave the cortex to reach subcortical and cortical long-range structures. Although several exceptions to this model have been described, neurons in layer 4 are still considered to establish only local (i.e., interlaminar and short-range) connections. Here, taking advantage of anatomic, electrophysiological, and optogenetic techniques, we describe, for the first time, a long-range corticostriatal class of pyramidal neurons in layer 4 (CS-L4) of the mouse auditory cortex that receive direct thalamic inputs. The CS-L4 neurons are embedded in a feedforward inhibitory circuit involving local parvalbumin neurons and establish connections in the posterior striatum in yet another feedforward inhibitory thalamo→cortico(L4)→striatal circuit which pot...

Down syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from medial septum to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in male Ts65Dn mice compared with their male nontrisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However, we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus is profoundly altered in these mice. Since the phasic organization of place cell activity and gamma oscillations ...

The axon initial segment (AIS), nodes of Ranvier, and the oligodendrocyte-derived myelin sheath have significant influence on the firing patterns of neurons and the faithful, coordinated transmission of action potentials (APs) to downstream brain regions. In the olfactory bulb (OB), olfactory discrimination tasks lead to adaptive changes in cell firing patterns, and the output signals must reliably travel large distances to other brain regions along highly myelinated tracts. Whether myelinated axons adapt to facilitate olfactory sensory processing is unknown. Here, we investigate the morphology and physiology of mitral cell (MC) axons in the olfactory system of adult male and female mice and show that unilateral sensory deprivation causes system-wide adaptations in axonal morphology and myelin thickness. MC spiking patterns and APs also adapted to sensory deprivation. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to re...

Mossy cells (MCs) of the dentate gyrus (DG) are key components of an excitatory associative circuit established by reciprocal connections with dentate granule cells (GCs). MCs are implicated in place field encoding, pattern separation and novelty detection, as well as in brain disorders such as temporal lobe epilepsy and depression. Despite their functional relevance, little is known about the determinants that control MC activity. Here, we examined whether MCs express functional kainate receptors (KARs), a subtype of glutamate receptors involved in neuronal development, synaptic transmission, and epilepsy. Using mouse hippocampal slices, we found that bath application of submicromolar and micromolar concentrations of the KAR agonist kainic acid induced inward currents and robust MC firing. These effects were abolished in GluK2 KO mice, indicating the presence of functional GluK2-containing KARs in MCs. In contrast to CA3 pyramidal cells, which are structurally and functionally similar to MCs and express s...

The NMDA subtype glutamate receptors (NMDARs) play important roles in both physiological and pathological processes in the brain. Comparing to their critical roles in synaptic modifications and excitotoxicity in excitatory neurons, much less is understood about the functional contributions of NMDARs to the inhibitory GABAergic neurons. By using selective NMDAR inhibitors and potentiators, we here show that NMDARs bi-directionally modulate the intrinsic excitability (defined as spontaneous/evoked spiking activity and EPSP-spike coupling) in inhibitory GABAergic neurons in adult male and female mice. This modulation depends on GluN2C/2D- but not GluN2A/2B-containing NMDARs. We further show that NMDAR modulator EU1794-4 mostly enhances extrasynaptic NMDAR activity, and by using it we demonstrate a significant contribution of extrasynaptic NMDARs to the modulation of intrinsic excitability in inhibitory neurons. Altogether, this bidirectional modulation of intrinsic excitability reveals a previously less appre...

Oxytocin (OXT) neurons in paraventricular nucleus of hypothalamus (PVN) are involved in modulating multiple functions, including social, maternal, feeding, and emotional related behaviors. PVN OXT neurons are canonically classified into magnocellular (Magno) and parvocellular (Parvo) subtypes. However, morpho-electric properties and the diversity of PVN OXT neurons are not well investigated. In this study, we profiled the morpho-electric properties of PVN OXT neurons by combining transgenic mice, electrophysiological recording, morphologic reconstruction, and unsupervised clustering analyses. Total 224 PVN OXT neurons from 23 mice were recorded and used for analyses in this study, and 29 morpho-electric parameters were measured. Magno and Parvo OXT neurons have prominent differences in their morpho-electric features, and PVN OXT neurons in male and female mice share similar neuronal properties. Some morpho-electric features of PVN OXT neurons, especially Magno neurons, exhibit significant diverse changes a...

Listeners with sensorineural hearing loss (SNHL) struggle to understand speech, especially in noise, despite audibility compensation. These real-world suprathreshold deficits are hypothesized to arise from degraded frequency tuning and reduced temporal-coding precision; however, peripheral neurophysiological studies testing these hypotheses have been largely limited to in-quiet artificial vowels. Here, we measured single auditory-nerve-fiber responses to a connected speech sentence in noise from anesthetized male chinchillas with normal hearing (NH) or noise-induced hearing loss (NIHL). Our results demonstrated that temporal precision was not degraded following acoustic trauma, and furthermore that sharpness of cochlear frequency tuning was not the major factor affecting impaired peripheral coding of connected speech in noise. Rather, the loss of cochlear tonotopy, a hallmark of NH, contributed the most to both consonant-coding and vowel-coding degradations. Because distorted tonotopy varies in degree acro...

Sensory experience during a critical period alters sensory cortical responses and organization. We find that the earliest sound-driven activity in the mouse auditory cortex (ACX) starts before ear-canal opening (ECO). The effects of auditory experience before ECO on ACX development are unknown. We find that in mouse ACX subplate neurons (SPNs), crucial in thalamocortical maturation, respond to sounds before ECO showing oddball selectivity. Before ECO, SPNs are more selective to oddball sounds in auditory streams than thalamo-recipient layer 4 (L4) neurons and not after ECO. We hypothesize that SPN's oddball selectivity can direct the development of L4 responses before ECO. Exposing mice, of either sex, before ECO to a rarely occurring tone in a stream of another tone occurring frequently leads to strengthening the adult cortical representation of the rare tone, but not that of the frequent tone. Results of control exposure experiments at multiple developmental windows that also use only a single tone corro...