Journal of Neuroscience最新文献

The mammalian cochlea receives efferent feedback from the brain. Many functions for this feedback have been hypothesized, including on short timescales, such as mediating attentional states, and long timescales, such as buffering acoustic trauma. Testing these hypotheses has been impeded by an inability to make direct measurements of efferent effects in awake animals. Here, we assessed the role of the medial olivocochlear (MOC) efferent nerve fibers on cochlear amplification by measuring organ of Corti vibratory responses to sound in both sexes of awake and anesthetized mice. We studied long-term effects by genetically ablating the efferents and/or afferents. Cochlear amplification increased with deafferentation using VGLUT3^-/- mice, but only when the efferents were intact, associated with increased activity within OHCs and supporting cells. Removing both the afferents and the efferents using VGLUT3^-/- Alpha9^-/- mice did not cause this effect. To test for short-term effects, we recorded sound-evoked vibrations while using pupillometry to measure neuromodulatory brain state. We found no state dependence of cochlear amplification or of the auditory brainstem response. However, state dependence was apparent in the downstream inferior colliculus. Thus, MOC efferents upregulate cochlear amplification chronically with hearing loss, but not acutely with brain state fluctuations. This pathway may partially compensate for hearing loss while mediating associated symptoms, such as tinnitus and hyperacusis.Significance Statement The functional role of efferent innervation of the mammalian cochlea has remained in question. Here we show that the medial olivocochlear efferent system chronically potentiates cochlear sensitivity in response to removing the afferent signal but does not affect sensitivity in response to fluctuations in pupil-indexed brain state. While partially compensating for hearing loss, the efferent-mediated chronic potentiation may also contribute to associated symptoms of hearing loss, such as tinnitus and hyperacusis.

It is recently shown that objects with long-term reward associations can be efficiently located during visual search. The neural mechanism for valuable object pop-out is unknown. In this work, we recorded neuronal responses in the ventrolateral prefrontal cortex (vlPFC) with known roles in visual search and reward processing in macaques while monkeys engaged in efficient vs inefficient visual search for high-value fractal objects (targets). Behavioral results and modeling using multi-alternative attention-modulated drift-diffusion (MADD) indicated that efficient search was concurrent with enhanced processing for peripheral objects. Notably, neural results showed response amplification and receptive field widening to peripherally presented targets in vlPFC during visual search. Both neural effects predict higher target detection and were found to be correlated with it. Our results suggest that value-driven efficient search independent of low-level visual features arises from reward-induced spatial processing enhancement of peripheral valuable objects.Significance Statement Rapid detection of rewarding objects can be essential for survival and reproduction in real life. However, finding valuable objects, among many others, can be time-consuming and slow. In this work, we reveal reward-related changes in the receptive fields of neurons within the prefrontal cortex of macaque monkeys that help them find valuable objects more efficiently. Such reward-related plasticity is shown to develop slowly for objects that are consistently associated with reward and challenges current theories of efficient search based on low-level visual features alone.

Auditory deficits are a well-known symptom in neuropsychiatric disorders such as schizophrenia. The non-competitive N-methyl-D-aspartate receptor antagonist ketamine has been used to model sensory and cognitive deficits in nonhuman primates, but its whole-brain effects remain largely unknown. Here we employed ultra-high-field fMRI at 9.4T in awake male and female marmoset monkeys (Callithrix jacchus) to compare brain activations to conspecific vocalizations, scrambled vocalizations, and non-vocal sounds following the administration of a subanesthetic dose of ketamine. Our findings reveal a broad suppression of activations across auditory regions following ketamine compared to saline. Additionally, we observed differential effects depending on the type of sound, with notable changes in the mediodorsal thalamus and anterior cingulate cortex, particularly during the processing of vocalizations. These findings suggest a potential overlap between the effects of ketamine and neural disruptions observed in schizophrenia, particularly affecting vocalization processing.Significant Statement This study explores the effects of ketamine, a compound known for its psychotomimetic effects that mimic those of neuropsychiatric disorders like schizophrenia, on auditory processing in common marmosets using ultra-high-field fMRI. We reveal a global suppression of neural activity across auditory regions under ketamine, with varying effects depending on the sound type in certain regions. Notably, the mediodorsal thalamus showed significant susceptibility in processing socially relevant sounds. These findings suggest parallels between ketamine's impact and auditory processing disruptions seen in schizophrenia.

Zebra finches sing individually unique songs and recognize conspecific songs and individual identities in songs. Their songs comprise several syllables/elements that share acoustic features within the species, with unique sequential arrangements. However, the neuronal mechanisms underlying the detection of individual differences and species specificity have yet to be elucidated. Herein, we examined the neuronal auditory responsiveness of neurons in higher auditory area, the caudal nidopallium (NCM), to songs and their elements in male zebra finches to understand the mechanism for detecting species and individual identities in zebra finch songs. We found that various adult male zebra finch songs share acoustically similar song elements but differ in their sequential arrangement between individuals. The broader spiking (BS) neurons in the NCM detected only a small subset of zebra finch songs, whereas NCM BS neurons, as a neuronal ensemble, responded to all zebra finch songs. Notably, distinct combinations of BS neurons responded to each of the 18 presented songs in one bird. Subsets of NCM BS neurons were sensitive to sequential arrangements of species-specific elements, which dramatically increasing the capacity for song variation with a limited number of species-specific elements. The naïve Bayes decoder analysis further showed that the response of sequence-sensitive BS neurons increased the accuracy of song stimulus predictions based on the response strength of neuronal ensembles. Our results suggest the neuronal mechanisms that NCM neurons as an ensemble decode the individual identities of songs, while each neuron detects a small subset of song elements and their sequential arrangement.Significance statement Zebra finches develop unique songs by learning from tutors. Various zebra finch songs consist of repeats of species-specific syllable elements that differ in their sequential arrangements. In vivo, single-unit electrophysiological recordings from neurons in the zebra finch's higher auditory area (caudal nidopallium [NCM]) revealed that each broad-spiking (BS) NCM neuron responded to a small subset of the zebra finch songs. However, a NCM neuronal ensemble detected all the songs. Some NCM BS neurons responded sensitively to sequential song element arrangement, which increased the prediction accuracy in the naïve Bayes decoder analysis. These findings suggest a neuronal mechanism for discriminating individual song variations in NCM neuronal ensembles, in which each neuron detects small subsets of song elements and their sequential arrangements.

Diabetic neuropathic pain (DNP) is a common chronic complication of diabetes mellitus and a clinically common form of neuropathic pain. The thalamus is an important center for the conduction and modulation of nociceptive signals. The paraventricular thalamic nucleus (PVT) is an important midline nucleus of the thalamus involved in sensory processing, but the specific role of PVT astrocytes and GABAergic neurons in DNP remains unclear. Here, we examined the activity of PVT astrocytes and neurons at various time points during the development of DNP by fluorescence immunohistochemistry and found that the activity of PVT astrocytes was significantly increased while that of PVT neurons was significantly decreased 14 d after streptozotocin injection in male rats. The inhibition of PVT astrocytes by chemogenetic manipulation relieved mechanical allodynia in male DNP model rats, whereas the activation of PVT astrocytes induced mechanical allodynia in normal male rats. Interestingly, chemogenetic activation of GABAergic neurons in the PVT alleviated mechanical allodynia in male DNP model rats, whereas chemogenetic inhibition of GABAergic neurons in the PVT induced mechanical allodynia in normal male rats. These data demonstrate the distinct roles of PVT astrocytes and GABAergic neurons in modulating DNP, revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.

The structure and function of the brain and cardiovascular system change over the lifespan. In this study, we aim to establish the extent to which age-related changes in these two vital organs are linked. Utilizing normative models and data from the UK Biobank, we estimate biological ages for the brain and heart for 2,904 middle-aged and older healthy adults, including both males and females. Biological ages were based on multiple structural, morphological, and functional features derived from brain and cardiovascular imaging modalities. We find that cardiovascular aging, particularly aging of its functional capacity and physiology, is selectively associated with the aging of specific brain networks, including the salience, default mode, and somatomotor networks as well as the subcortex. Our work provides unique insight into brain–heart relationships and may facilitate an improved understanding of the increased co-occurrence of brain and heart diseases in aging.

The ability of neurons to sense and respond to damage is crucial for maintaining homeostasis and facilitating nervous system repair. For some cell types, notably dorsal root ganglia and retinal ganglion cells, extensive profiling has uncovered a significant transcriptional response to axon injury, which influences survival and regenerative outcomes. In contrast, the injury responses of most supraspinal cell types, which display limited regeneration after spinal damage, remain mostly unknown. In this study, we used single-nuclei sequencing in adult male and female mice to profile the transcriptional responses of diverse supraspinal cell types to spinal injury. Surprisingly, thoracic spinal injury induced only modest changes in gene expression across all populations, including corticospinal tract (CST) neurons. Additionally, CST neurons exhibited minimal response to cervical injury but showed a much stronger reaction to intracortical axotomy, with upregulation of numerous regeneration and apoptosis-related transcripts shared with injured DRG and RGC neurons. Thus, the muted response of CST neurons to spinal injury is linked to the injury's distal location, rather than intrinsic cellular characteristics. More broadly, these findings indicate that a central challenge for enhancing regeneration after a spinal injury is the limited detection of distant injuries and the subsequent modest baseline neuronal response.

Extracellular matrix (ECM) is a network of macromolecules which has two forms-perineuronal nets (PNNs) and a diffuse ECM (dECM)-both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan (HA) synthesis, we found downregulated staining for PNNs, HA, chondroitin sulfate proteoglycans, and glial fibrillary acidic protein. These changes were enhanced after 4 and 6 months and were reversible after a normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in the somatosensory cortex by 35%, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging revealed a decrease of mean diffusivity and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum, and spinal cord. This study shows the increase in ECS volume, a loss of FA, and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell-to-cell communication, and neural plasticity.

Pyramidal cells (PCs) in CA1 hippocampus can be classified by their radial position as deep or superficial and organize into subtype-specific circuits necessary for differential information processing. Specifically, superficial PCs receive fewer inhibitory synapses from parvalbumin (PV)-expressing interneurons than deep PCs, resulting in weaker feedforward inhibition of input from CA3 Schaffer collaterals. Using mice, we investigated mechanisms underlying CA1 PC differentiation and the development of this inhibitory circuit motif. We found that the transcriptional regulator SATB2, which is necessary for pyramidal cell differentiation in the neocortex, is selectively expressed in superficial PCs during early postnatal development. To investigate its role in CA1, we conditionally knocked out Satb2 from pyramidal cells during embryonic development using both male and female Emx1^IRES-Cre; Satb2^flox/flox mice. Loss of Satb2 resulted in increased feedforward inhibition of CA3 Schaffer collateral input to superficial PCs, which matched that observed to deep PCs in control mice. Using paired whole-cell recordings between PCs and PV+ interneurons, we found this was due to an increase in the strength of unitary inhibitory synaptic connections from PV+ interneurons to mutant superficial PCs. Regulation of synapse strength was restricted to inhibitory synapses; excitatory synaptic connections from CA3 to CA1 PCs and CA1 PCs to PV+ interneurons were not affected by loss of Satb2 Finally, we show that SATB2 expression in superficial PCs is necessary to suppress the formation of synapses from PV+ interneurons during synaptogenesis. Thus, early postnatal expression of SATB2 in superficial PCs is necessary for the development of biased feedforward inhibition in CA1.