Journal of Neuroscience最新文献

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic that is being investigated for the treatment of psychiatric disorders. Although the neurophysiological effects of DMT in humans are well characterized, similar studies in animal models and data on the neurochemical effects of DMT are generally lacking, which are critical for a mechanistic understanding. Here, we combined behavioral analysis, high-density (32-channel) electroencephalography, and ultrahigh-performance liquid chromatography-tandem mass spectrometry to simultaneously quantify changes in behavior, cortical neural dynamics, and levels of 17 neurochemicals in medial prefrontal and somatosensory cortices before, during, and after intravenous administration of DMT (0.75, 3.75, 7.5 mg/kg) in male and female adult rats. All three doses of DMT produced head twitch response with most twitches observed after the low dose. DMT caused dose-dependent increases in serotonin and dopamine levels in both cortical sites, a reduction in EEG spectral power in theta (4-10 Hz) and low gamma (25-55 Hz), and an increase in spectral power in delta (1-4 Hz), medium gamma (65-115 Hz), and high gamma (125-155 Hz) bands. Functional connectivity decreased in the delta band and increased across the gamma bands. We detected cortical DMT in baseline wake condition in 70-80% of the animals tested at levels comparable to serotonin and dopamine, which, together with a previous study in the occipital cortex, motivates cross-species studies to confirm endogenous presence of DMT. This study represents one of the most comprehensive characterizations of psychedelic drug action in rats and the first to be conducted with intravenous DMT.

To encode a cognitive map of an environment, a navigator must be able to integrate across perceptual views corresponding to the same place. This can be done in two ways: first, by integrating across the panorama of views obtainable at a single vantage point, and second, by integrating across views of a distal location containing a landmark that is visible from multiple vantage points. We tested the hypothesis that these two viewpoint integration processes are mediated by different neuroanatomical substrates. Male and female human participants were familiarized with a route through a virtual city. Storefronts along the route were pairwise associated in two ways: either by being on different buildings directly across the street from each other (panoramic association) or by being on different sides of the same building facing different streets (landmark association). Participants were then scanned with fMRI while they viewed the storefronts in isolation and performed a spatial memory task. Multivoxel pattern analyses revealed coding of panoramic associations in the retrosplenial complex and several other regions within the medial and lateral parietal lobe including the medial place-memory area, lateral place-memory area, and the newly described superior parietal place-memory area. In contrast, landmark associations were coded in the parahippocampal place area. These results demonstrate the existence of two neural mechanisms for integrating across views to represent places as either the observer's location (same panorama) or the observed location (same landmark).

To navigate the world, we store knowledge about relationships between concepts and retrieve this information flexibly to suit our goals. The semantic control network, comprising left inferior frontal gyrus (IFG) and posterior middle temporal gyrus (pMTG), is thought to orchestrate this flexible retrieval by modulating sensory inputs. However, interactions between semantic control and input regions are not sufficiently understood. Moreover, pMTG's well-formed structural connections to IFG and visual cortex suggest it as a candidate region to integrate control and input processes. We used magnetoencephalography to investigate oscillatory dynamics during semantic decisions to pairs of words, when participants (both sexes) did or did not know the type of semantic relation between them. IFG showed increases and decreases in oscillatory activity to prior task knowledge, while pMTG only showed positive task knowledge effects. Furthermore, IFG provided sustained feedback to pMTG when task goals were known, while in the absence of goals this feedback was delayed until receiving bottom-up input from the second word. This goal-dependent feedback coincided with an earlier onset of feedforward signalling from visual cortex to pMTG, indicating rapid retrieval of task-relevant features. This pattern supports a model of semantic cognition in which pMTG integrates top-down control from IFG with bottom-up input from visual cortex to activate task-relevant semantic representations. Our findings elucidate the separate roles of anterior and posterior components of the semantic control network and reveal the spectro-temporal cascade of interactions between semantic and visual regions that underlie our ability to flexibly adapt cognition to the current goals.Significance Statement Using magnetoencephalography, we characterize the spectro-temporal dynamics that underlie our ability to flexibly adapt semantic cognition to the current context and goals. We find that semantic goals increase oscillatory activity in IFG and pMTG, and ultimately facilitate visual processing. Effective connectivity analyses reveal more sustained feedback from IFG to pMTG, and more rapid feedforward signalling from visual cortex to pMTG, resulting in rapid retrieval when semantic goals are known. Crucially, our findings suggest differential roles for the two semantic control regions: while IFG controls goal-dependent retrieval, pMTG integrates top-down information from IFG with bottom-up visual input.

The brain computes the spatiotopic position of touch by integrating tactile and proprioceptive signals (i.e., tactile remapping). While it is often assumed that the spatiotopic touch location is mapped into extrinsic, limb-independent coordinates, an alternative view proposes that touch is remapped into intrinsic, limb-specific coordinates. To test between these hypotheses, we used electroencephalography (EEG) and a novel tactile stimulation paradigm in which participants (N = 20, 19 females) received touch on their hands positioned at various locations relative to the body. Previous findings suggest that neural activity in primate sensorimotor and parietal regions monotonically encodes limb position, with their sustained firing rates increasing or decreasing across the workspace. These amplitude gradients, detectable at the population level in somatosensory evoked potentials, can be used to test predictions from each spatiotopic coding scheme. If touch is coded extrinsically, neural gradients should reflect changes of the external stimulus location, regardless of the limb. If coded intrinsically, gradients should be tied to the position of each limb and mirror each other between hands. Both univariate and multivariate EEG analyses found no evidence for extrinsic coding. Instead, we observed neural signatures of limb-specific, intrinsic spatiotopic coding, with the earliest emerging ∼160 ms after touch in centroparietal channels, later shifting to frontotemporal and parieto-occipital channels. Furthermore, a population-based neural network model of tactile remapping successfully reproduced the observed gradient patterns. These results show that the human brain localizes touch using an intrinsic, limb-specific spatial code, challenging the dominant assumption of extrinsic encoding in tactile remapping.

The brain can be conceptualized as a control system facilitating transitions between states, such as from rest to motor activity. Applying network control theory to measurements of brain signals enables characterization of brain dynamics through control properties. However, most prior studies that have applied network control theory have evaluated brain dynamics under unperturbed conditions, neglecting the critical role of external perturbations in accurate system identification. In this study, we combine a perturbation input paradigm with a network control theory framework and propose a novel method for estimating the controllability Gramian matrix in a simple, theoretically grounded manner. This method provides insights into brain dynamics, including overall controllability (quantified by the Gramian's eigenvalues) and specific controllable directions (represented by its eigenvectors). As a proof of concept, we applied our method to transcranial magnetic stimulation-induced electroencephalographic responses across four motor-related states and two resting states. We found that states such as open-eye rest, closed-eye rest, and motor-related states were more effectively differentiated using controllable directions than overall controllability. However, certain states, like motor execution and motor imagery, remained indistinguishable using these measures. These findings indicate that some brain states differ in their intrinsic control properties as dynamical systems, while others share similarities. This study underscores the value of control theory-based analyses in quantitatively how intrinsic brain states shape the brain's responses to stimulation, providing deeper insights into the dynamic properties of these states. This methodology holds promise for diverse applications, including characterizing individual response variability and identifying conditions for optimal stimulation efficacy.

The rate of cognitive decline in Alzheimer's disease (AD) varies considerably from person to person. Numerous epidemiological studies point to the protective effects of cognitive, social, and physical enrichment as potential mediators of cognitive decline in AD; however, there is much debate as to the mechanism underlying these protective effects. The retrosplenial cortex (RSC) is one of the earliest brain regions with impaired functions during AD pathogenesis, and its activity is affected by cognitive, social, and physical stimulation, making it a particularly interesting region to investigate the influences of an enriched lifestyle on AD pathogenesis. In the current study, we use the 5xFAD mouse mode of AD to examine the impact of enriched housing conditions on cognitive function in AD and the viability of a particularly vulnerable cell population within the RSC - parvalbumin interneurons (PV-INs). Enriched housing conditions improved cognitive performance in female 5xFAD mice. These changes in cognitive performance coincided with restored functional connectivity of the RSC and preserved PV-IN density within this region. Along with preserved PV-IN density, there was an increase in the density of Wisteria floribunda agglutinin-positive perineuronal nets (WFA+PNNs) across the RSC of 5xFAD mice housed in enriched conditions. Direct manipulation of WFA+PNNs revealed that these extracellular matrix structures protect PV-INs from amyloid toxicity and may be the mechanisms underlying the protective effects of enrichment. Together, these results provide support for the WFA+PNN-mediated maintenance of PV-INs in the RSC as a potential mechanism mediating the protective effects of enrichment against cognitive decline in AD.Significance statement The rate of progression of Alzheimer's Disease is highly variable. The extent to which individuals engage in an enriched lifestyle is one factor that has been proposed to promote cognitive resiliency to AD pathology. Understanding how enrichment promotes resiliency is critical for promoting healthy cognitive aging. Recent work has demonstrated that the retrosplenial cortex, and especially parvalbumin interneurons in this region are highly vulnerable to AD pathology and their impairments relate to early cognitive impairments. Here, we show that environmental enrichment promotes cognitive performance and the survival of parvalbumin interneurons in the retrosplenial cortex through a mechanism dependent on perineuronal net maintenance. These results help to explain the mechanisms that mediate the influence of environmental enrichment on cognitive resiliency.

Many studies have demonstrated that the basolateral complex of the amygdala (BLA) can facilitate offline consolidation processes in the hippocampus. However, an open question is how online neuronal oscillations in these regions dynamically couple at the moment of encoding to enable an episodic prioritization for important ecologically relevant stimuli. In the current study, local field potentials (LFPs) were recorded in the BLA and hippocampus (ventral CA1) of female rats as they spontaneously explored many novel and repeated plant-based odors and rat urine odors, which convey ecologically relevant information about conspecifics. Rats' estrous cycle was tracked and used to estimate sexual receptivity. Moments of exploring urine odors, particularly from male donors, were associated with different neural activity in the BLA and hippocampus versus plant-based odors, activity that also depended on the novelty of the odors as well as the rats' sexual receptivity. Specifically, prominent slow gamma (20-50 Hz) oscillations during odor exploration showed a BLA-to-hippocampus directionality and were associated with odor novelty, odor category (male urine vs. female urine vs. plant-based odors), and better subsequent memory. Spiking-associated (150-200 Hz) activity in the LFPs was also influenced by odor novelty and odor category and was significantly higher in both the BLA and hippocampus on days for which the rats were sexually receptive. Thus, stimulus novelty and ecological relevance combined with the rats' emotional state to shape the neural correlates of prioritized encoding. The results are discussed in terms of endogenous mechanisms of memory enhancement for important to-be-remembered stimuli.Significance Statement The amygdala and hippocampus play complementary roles in making important information more memorable. A fundamental question is how neuronal activity in these regions becomes coordinated when encountering to-be-remembered information. We recorded neuronal activity in these regions as female rats encountered many new and repeated urine odor samples from other male and female rats. Urine odors convey key information about other rats. Investigating urine odors, particularly from males, led to different neural activity in the amygdala and hippocampus versus plant-based odors, activity that was also associated with the novelty of the odors, the rats' sexual receptivity, and how well remembered the odors were. Stimulus novelty and biological significance may combine with one's emotional state to determine the neural correlates of memorability.

Fast-spiking, non-adaptive inhibitory neurons in the thalamic reticular nucleus (TRN) critically gate the reciprocal communication between the thalamus and the cortex. Parvalbumin (PV) neurons express high levels of PV, the sole role of which appears to be calcium buffering. The significance of the PV protein - and its related high calcium-buffering capacity - under pathological conditions, especially in various neuropsychiatric disorders, is underappreciated. Deficiency of SHANK3, an important neuronal protein containing ankyrin, SH3, and PDZ, three canonical domains for protein recognition, causes behavioral changes relevant to autism spectrum disorders (ASD). Here we report TRN PV neurons of Shank3-/- (exon 4-22 deletion) mice of either sex exhibit pronounced increases in burst firing occurrence, decreased tonic firing frequency, and faster dendritic calcium transient decay. We pinpointed reduced PV expression as the culprit and used the added-buffer approach to confirm the decrease in calcium-buffering capacity in mutant neurons. Conversely, supplementing Shank3-/- PV neurons with extra EGTA reversed the abnormal action potential (AP) firing. In addition, the PV neurons from HCN2-/- mice exhibit consistent changes in neuronal excitability, PV expression, and calcium signaling. Together with the study of dopaminergic (DA) neurons in the ventral tegmental area (VTA), these results uncover reduced PV expression, calcium-buffering capacity, and altered neuronal excitability in Shank3-/- and HCN2-/- mice. This pathway, downstream of Shank3 deficiency and HCN channelopathy, may form an important pathological basis not only for ASD but also other neuropsychiatric disorders.Significance Statement SHANK3 is a scaffolding protein that is highly enriched in the postsynaptic density (PSD) of synapses. Mutations and deletions of the SHANK3 gene are directly connected to Phelan-McDermid syndrome (PMS) and autism spectrum disorders (ASD). However, the links between genetic alterations and abnormalities at the cellular, network, and behavioral levels remain unclear. This study uncovered abnormal physiological changes in inhibitory neurons in the thalamus. A definitive link at the cellular level is established between the Shank3 protein deficiency and the pathological basis of related neuropsychiatric disorders.

Episodic memory retrieval engages both sensory reinstatement and internally transformed representations. Due to modality-specific processing, auditory and visual memories may differ in their reliance on these mechanisms. We used functional magnetic resonance imaging (fMRI) and multivoxel pattern analyses (MVPA) to examine how 25 participants (12 males and 13 females) encoded and retrieved naturalistic sounds and videos. Both auditory and visual targets reinstated event-specific fine activation patterns in the association cortex during retrieval, and reinstatement strength correlates with subjective memory vividness. However, after removing encoding traces, auditory episodes showed a markedly larger reliance on internally transformed traces than visual episodes, quantified by "reinstatement-free" retrieval-retrieval similarity. Sensory reinstatement correlated more with the (detail-related) posterior hippocampus, while internal representations also correlated with the (gist-related) anterior hippocampus. Furthermore, temporal voice areas preserved gist-level (human versus non-human) information from encoding to retrieval, whereas fusiform face representations degraded. These findings reveal that auditory and visual memories share a common sensory reinstatement mechanism, but differ in the neural mechanism that supports retrieval, with participants favoring gist over perceptual details during auditory memory retrieval.Significance Statement How does the brain retrieve memories of sights and sounds, and why do their subjective qualities differ? Behavioral work suggests auditory memories may be less vivid but longer-lasting than visual memories. Using fMRI and multivoxel pattern analysis during the recall of naturalistic soundscapes and videos, we showed that auditory episodes, like visual ones, reinstated item-specific activity patterns in higher-order sensory cortex, and that reinstatement fidelity tracks subjective vividness. Critically, however, auditory retrieval relies more heavily on internally generated, gist-like representations that recruit the anterior hippocampus, whereas visual retrieval preserves richer perceptual details. These findings reveal a shared yet flexibly weighted retrieval architecture across senses, account for behavioral asymmetries in memory, and inform sensory-tailored strategies for education, ageing, and neurorehabilitation.