Recent studies suggest some hippocampal (HC) neurons respond to passively presented sounds in naïve subjects, but the specificity and prevalence of these responses remain unclear. We used Neuropixels probes to record unit activity across layers in mid-ventral HC and auditory cortex (ACtx) of awake, untrained mice (male and female) while presenting diverse sounds at typical environmental levels (65-70 dB SPL). A subset of HC neurons exhibited reliable, short-latency responses to passive sounds, including tones and broadband noise. HC units showed evidence of tuning for tone frequency but not spectrotemporal features in continuous dynamic moving ripples. Across sound types, HC responses overwhelmingly occurred at stimulus onset; they quickly adapted to continuous sounds and did not respond at sound offset. Among all sounds tested, broadband noise was most effective at driving HC activity. Spectral manipulations indicated response prevalence scaled with increasing spectral bandwidth and density. Similar responses were also observed for visual flash and contrast modulated noise movies, although these were less common than for broadband noise. Sound-evoked face movements, quantified by total face motion energy (FME), correlated with population-level HC activity. However, many individual units responded regardless of FME strength, suggesting both auditory and motor-correlated inputs. Together, our results show that abrupt sound onsets are sufficient to activate many HC neurons in the absence of learning or behavioral engagement. This supports a role for HC in detecting salient environmental changes and supports the idea that auditory inputs contribute directly to HC function.Significance statement Hippocampus is critical for learning and memory, but its role in sensory processing is less understood. Here, we show many hippocampal neurons in awake, untrained mice respond to passive sounds, especially broadband noise. Sound onsets - transitions from silence to sound - are critical for these responses, suggesting a role in detecting abrupt, salient environmental changes. Consistent with this possibility, some units also responded to visual events, though fewer than responded to noise. In contrast to auditory cortex, hippocampal units were not reliably tuned for spectrotemporal modulation features, suggesting independent functional roles. The prevalence of passive auditory processing in hippocampus builds on previous work suggesting hearing may interact with general cognitive health.
Loss of function variants of SCN1B are associated with a range of developmental and epileptic encephalopathies (DEEs), including Dravet syndrome. These DEEs feature a wide range of severe neurological disabilities, including changes to social, motor, mood, sleep, and cognitive function which are notoriously difficult to treat, and high rates of early mortality. While the symptomology of SCN1B-associated DEEs indicates broad changes in neural function, most research has focused on epilepsy-related brain structures and function. Mechanistic studies of SCN1B/Scn1b have delineated diverse roles in development and adult maintenance of neural function, via cell adhesion, ion channel regulation, and other intra- and extra-cellular actions. However, use of mouse models is limited as knock-out of Scn1b, globally and even in some cell-specific models (e.g., parvalbumin+ interneuron-specific knock-out) in adult mice, leads to severe and progressive epilepsy, health deterioration, and 100% mortality within weeks. Here, we report findings using male and female mice of a novel transgenic line in which Scn1b was specifically deleted in cerebellar Purkinje cells. Unlike most existing models, these mice survive and thrive. However, we quantified marked decrements to Purkinje cell physiology as well as motor, social, and cognitive dysfunction. Our data indicates that cerebellar Purkinje cells are an important node for dysfunction and neural disabilities in SCN1B-related DEEs and combined with previous work identify this as a potentially vital site for understanding mechanisms of DEEs and developing therapies that can treat these disorders holistically.
Heterogeneity of presynaptic input and postsynaptic intrinsic excitability are two major variables that regulate neuronal firing rates and patterns. Yet, little is known about how these variables interplay to diversify the fidelity of excitation-spike coupling. To investigate their reciprocal relationship, we took advantage of the one-to-one innervation of mature calyx of Held-principal neuron synapses at the medial nucleus of the trapezoid body (MNTB) in the auditory brainstem of male and female mice. Given that sustainability of synaptic drive is directly correlated with the morphological complexity of presynaptic calyces, we characterized the intrinsic excitability of postsynaptic neurons with morphologically identified inputs. We discovered that morphologically simple calyces (stalks and ≤10 swellings) providing weaker synaptic drive preferentially innervate principal neurons that exhibit lower stimulation-spike coupling fidelity and display phasic firing patterns, while neurons contacted by complex calyces (stalks and >20 swellings) providing stronger synaptic drive exhibit higher stimulation-spike coupling fidelity and are predominantly associated with tonic firing. Phasic and tonic firing neurons have similar action potential shape and composition of low-threshold Kv1 and high-threshold Kv3 potassium currents but display marked differences in their input resistance and resting potassium conductance. Our results support a model in which a postsynaptic gradient of leak potassium channel density complements the presynaptic morpho-functional continuum to create an extended dynamic range of MNTB outputs. This synergy expands the coding capacity within a single population of neurons and supports multiple streams of auditory processing.
Humans are skilled at recognizing everyday objects from pictures, even if we have never encountered the depicted object in real life. However, if we have encountered an object, how does that real-world experience affect the representation of its photographic image in the human brain? We developed a paradigm that involved brief real-world manual exploration of everyday objects prior to the measurement of brain activity with fMRI while viewing pictures of those objects (40 participants, 28 females). We found that while object-responsive regions in the lateral occipital and ventral temporal cortex contained robust visual representations of specific objects, those representations were not modulated by brief real-world exploration. However, there was an effect of visual experience in object-responsive regions in the form of repetition suppression of the BOLD response over repeated presentations of the object images. Real-world experience with an object produced foci of increased activation in the medial parietal and posterior cingulate cortex, regions that have previously been associated with the encoding and retrieval of remembered items in explicit memory paradigms. Our discovery that these regions are engaged during spontaneous recognition of real-world objects from their 2D image demonstrates that modulation of activity in medial regions by familiarity is neither stimulus nor task-specific. Overall, our results support separable coding in the human brain of the visual appearance of an object from the associations gained via real-world experience. The richness of object representations beyond their photographic image has important implications for understanding object recognition in the human brain and in computational models.
At autopsy, >95% of ALS cases display a redistribution of the essential RNA binding protein TDP-43 from the nucleus into cytoplasmic aggregates. The mislocalization and aggregation of TDP-43 is believed to be a key pathological driver in ALS. Due to its vital role in basic cellular mechanisms, direct depletion of TDP-43 is unlikely to lead to a promising therapy. Therefore, we have explored the utility of identifying genes that modify its mislocalization or aggregation. We have previously shown that loss of rad-23 improves locomotor deficits in TDP-43 C. elegans models of disease and increases the degradation rate of TDP-43 in cellular models. To understand the mechanism through which these protective effects occur, we generated an inducible mutant TDP-43 HEK293 cell line. We find that knockdown of RAD23A reduces insoluble TDP-43 levels in this model and primary rat cortical neurons expressing human TDP-43A315T Utilizing a discovery-based proteomics approach, we then explored how loss of RAD23A remodels the proteome. Through this proteomic screen, we identified USP13, a deubiquitinase, as a new potent modifier of TDP-43 induced aggregation and cytotoxicity. We find that knockdown of USP13 reduces the abundance of sarkosyl insoluble mTDP-43 in both our HEK293 model and primary rat neurons, reduces cell death in primary rat motor neurons, and improves locomotor deficits in C. elegans ALS models.Significance Statement Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease (NDD) with no effective therapies. The mislocalization and aggregation of TAR DNA binding protein 43 (TDP-43) is a key pathological marker of ALS and other NDDs. Due to its vital functions, targeted therapeutic reduction of TDP-43 could be problematic. Here, we have explored the utility of targeting modifier genes. We find that knockdown of two members of the ubiquitin proteasome system, RAD23A and USP13, enhance TDP-43 solubility and decrease TDP-43 induced neurotoxicity.
The role of P2X4, one of the most abundant ionotropic purinergic receptors in the central nervous system, is explored in the context of auditory function. We observed, by using constitutive and conditional P2X4mCherryIN knock-in adult mouse models of either sex, a specific high expression of mCherry-tagged P2X4 in living cochlear outer hair cells (OHCs), from immature postnatal stages to adulthood. This P2X4-mCherry expression, confirmed by confocal immunofluorescence microscopy in wild-type (WT) mice, was mainly concentrated in the intracellular apical region of OHCs, in the area of Hensen's body, a lysosomal-rich region, specifically labeled with the fluorescent dye lysotracker. In addition, the basal cholinergic efferent synaptic region of the OHCs was found to express P2X4 at the cell membrane. Surprisingly, the assessment of the hearing function in constitutive P2X4 knock-out (P2X4KO) mice showed improved auditory brainstem responses (ABRs) with smaller latencies and lower thresholds. These P2X4KO mice, as well as conditional Myo15-Cre:P2X4KO mice, displayed enhanced distortion product otoacoustic emissions (DPOAEs), suggesting an improved electromechanical "amplification" activity by OHCs. These mutant animals showed reduced inhibition of DPOAEs by contralateral noise, consistent with a weaker inhibitory effect of the medial cholinergic olivocochlear (MOC) efferent circuit on OHCs. When P2X4KO mice were exposed to noise (white noise 95 dB SPL, 12 h), ABRs decreased and partially recovered much like WT mice, but DPOAEs showed faster recovery. We concluded that the MOC negative feedback modulation of cochlear micromechanics, in addition to involve Ca2+ permeable α9/α10 nicotinic receptors, also requires the activation of postsynaptic P2X4 receptors in OHCs.
GPR85/SREB2 is an exceptionally conserved orphan seven-transmembrane receptor with poorly understood biological function. Here, we combine genetic, imaging, transcriptomic, electrophysiological, and behavioral approaches in zebrafish to uncover the properties and roles of Gpr85 across development and adulthood. We show that, as in mammals, gpr85 is expressed in diverse neuronal populations within the central nervous system, retina, and intestine. Using a fluorochrome-tagged Gpr85 construct expressed in native domains, we provide the first in vivo evidence that Gpr85 is enriched at synaptic sites in both the brain and retina. Transcriptomic profiling of cerebellar granule cells (GCs) lacking Gpr85 reveals gene expression changes consistent with increased neuronal activity. Electrophysiological recordings from cerebellar slices confirm that Gpr85-deficient GCs exhibit heightened excitability. Functionally, Gpr85 loss enhances light-triggered motor responses in larval zebrafish. Together, these findings position Gpr85 as a synapse-enriched modulator of neuronal excitability and sensory-driven behavior, offering new insight into its roles.
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