Journal of Neuroscience最新文献

Fetal alcohol spectrum disorders (FASDs) are characterized by a range of physical, cognitive, and behavioral impairments. Determining how temporally specific alcohol exposure (AE) affects neural circuits is crucial to understanding the FASD phenotype. Third trimester AE can be modeled in rats by administering alcohol during the first two postnatal weeks, which damages the medial prefrontal cortex (mPFC) and hippocampus (HPC), structures whose functional interactions are required for working memory and executive function. Therefore, we hypothesized that AE during this period would impair working memory, disrupt choice behaviors, and alter mPFC-HPC oscillatory synchrony. To test this hypothesis, we recorded local field potentials from the mPFC and dorsal HPC as male and female AE and sham intubated (SI) rats performed a spatial working memory task in adulthood and implemented algorithms to detect vicarious trial and errors (VTEs), behaviors associated with deliberative decision-making. We found that, compared to the SI group, the AE group performed fewer VTEs and demonstrated a disturbed relationship between VTEs and choice outcomes, while spatial working memory was unimpaired. This behavioral disruption was accompanied by alterations to mPFC and HPC oscillatory activity in the theta and beta bands, respectively, and a reduced prevalence of mPFC-HPC synchronous events. When trained on multiple behavioral variables, a machine learning algorithm could accurately predict whether rats were in the AE or SI group, thus characterizing a potential phenotype following third trimester AE. Together, these findings indicate that third trimester AE disrupts mPFC-HPC oscillatory interactions and choice behaviors.Significance statement Fetal alcohol spectrum disorders (FASDs) occur at an alarmingly high rate worldwide. Prenatal alcohol exposure leads to significant perturbations in brain circuitry that are accompanied by cognitive deficits, including disrupted executive functioning and working memory. These deficits stem from structural changes within several key brain regions including the prefrontal cortex and hippocampus. To better understand the cognitive deficits observed in FASD patients, we employed a rodent model of alcohol exposure during the third trimester, a period when these regions are especially vulnerable to alcohol-induced damage. We show that alcohol exposure disrupts choice behaviors and prefrontal-hippocampal functional connectivity during a working memory task, identifying the prefrontal-hippocampal network as a potential therapeutic target in FASD treatment.

Opioids initiate dynamic maladaptation in brain reward and affect circuits that occur throughout chronic exposure and withdrawal that persist beyond cessation. Protracted abstinence is characterized by negative affective behaviors such as heightened anxiety, irritability, dysphoria, and anhedonia, which pose a significant risk factor for relapse. While the ventral tegmental area (VTA) and mu-opioid receptors (MORs) are critical for opioid reinforcement, the specific contributions of VTA^MOR neurons in mediating protracted abstinence-induced negative affect is not fully understood. In our study, we elucidate the role of VTA^MOR neurons in mediating negative affect and altered brain-wide neuronal activities following forced opioid exposure and abstinence in male and female mice. Utilizing a chronic oral morphine administration model, we observe increased social deficit, anxiety-related, and despair-like behaviors during protracted forced abstinence. VTA^MOR neurons show heightened neuronal FOS activation at the onset of withdrawal and connect to an array of brain regions that mediate reward and affective processes. Viral re-expression of MORs selectively within the VTA of MOR knockout mice demonstrates that the disrupted social interaction observed during protracted abstinence is facilitated by this neural population, without affecting other protracted abstinence behaviors. Lastly, VTA^MORs contribute to heightened neuronal FOS activation in the anterior cingulate cortex (ACC) in response to an acute morphine challenge, suggesting their unique role in modulating ACC-specific neuronal activity. These findings identify VTA^MOR neurons as critical modulators of low sociability during protracted abstinence and highlight their potential as a mechanistic target to alleviate negative affective behaviors associated with opioid abstinence.Significance statement The compelling urge for relief from negative affective states during long-term opioid abstinence presents a crucial challenge for maintaining abstinence. The ventral tegmental area (VTA) and its mu-opioid receptor-expressing (VTA^MOR) neurons represent a critical target of opioidergic action that underlie dependence and abstinence. Chronic activation of VTA^MOR neurons during opioid exposure induces maladaptations within these neurons and their structurally connected circuitries, which alter reward processing and contribute to negative affect. Using an oral morphine drinking paradigm to induce dependence, we demonstrate that withdrawal engages VTA^MOR neurons and identify this neuronal population as key mediators of opioid abstinence-induced social deficits. These findings hold promise to inform development of targeted therapies aimed at alleviating negative affective states associated with protracted opioid abstinence.

Adaptation affects neuronal responsivity and selectivity throughout the visual hierarchy. However, because most prior studies have tailored stimuli to a single brain area of interest, we have a poor understanding of how exposure to a particular image alters responsivity and tuning at different stages of visual processing. Here we assess how adaptation with naturalistic textures alters neuronal responsivity and selectivity in primary visual cortex (V1) and area V2 of macaque monkeys. Neurons in both areas respond to textures, but V2 neurons are sensitive to higher-order image statistics which do not strongly modulate V1 responsivity. We tested the specificity of adaptation in each area with textures and spectrally-matched 'noise' stimuli. Adaptation reduced responsivity in both V1 and V2, but only in V2 was the reduction dependent on the presence of higher-order texture statistics. Despite this specificity, the texture information provided by single neurons and populations was reduced after adaptation, in both V1 and V2. Our results suggest that adaptation effects for a given feature are induced at the stage of processing that tuning for that feature first arises and that stimulus-specific adaptation effects need not result in improved sensory encoding.Significance statement Nearly all sensory neurons adapt to recent input. However, how the adjustment triggered by a particular input is distributed across brain areas and how these changes contribute to sensory processing are poorly understood. Here we explore adaptation with naturalistic textures, for which neurons in primary visual cortex and area V2 have differing selectivity. Adaptation reduced responsivity in both areas, but the effects in V2 alone depended on the presence of the higher-level texture statistics to which V2 neurons are sensitive. Though prior work with simpler stimuli has argued that stimulus-specific adaptation improves stimulus discriminability, we found adaptation reduced texture information. Thus, adaptation need not improve visual encoding, suggesting its effects may serve some other purpose.

The influence of neural activity on astrocytes and their reciprocal interactions with neurons has emerged as an important modulator of synapse function. Astrocytes exhibit activity-dependent changes in gene expression, yet the molecular mechanisms by which neural activity is coupled to gene expression are not well understood. The molecular signaling pathway, Sonic hedgehog (Shh), mediates neuron-astrocyte communication and regulates the organization of cortical synapses. Here, we demonstrate that neural activity stimulates Shh signaling in cortical astrocytes and upregulates expression of Hevin and SPARC, astrocyte-derived molecules that modify synapses. Whisker stimulation in both male and female mice promotes activity-dependent Shh signaling selectively in the somatosensory, but not visual cortex, whereas sensory deprivation reduces Shh activity, demonstrating bidirectional regulation of the pathway by sensory experience. Selective loss of Shh signaling in astrocytes reduces expression of Hevin and SPARC and occludes activity-dependent synaptic plasticity. Taken together, these data identify Shh signaling as an activity-dependent, molecular signaling pathway that regulates astrocyte gene expression and promotes astrocyte modulation of synaptic plasticity.Significance statement Understanding how the nervous system orchestrates the complex cellular and molecular interactions that are necessary to adapt to changing environments is a fundamental goal in neuroscience. Neuronal adaption to novel experience is well characterized, however astrocytes are now recognized as key players in modulating synaptic function and plasticity. Like neurons, astrocytes exhibit activity-dependent gene expression. However, the mechanisms by which activity is coupled to gene expression are poorly defined. Here, we show that neural activity stimulates the molecular signaling pathway, Sonic hedgehog (Shh), in astrocytes. Shh signaling promotes expression of synapse-regulating genes and is required for astrocyte modulation of synaptic plasticity. Understanding how astrocytes contribute to synaptic plasticity sheds new light on how experience shapes brain function.

Goal-directed reaches give rise to dynamic neural activity across the brain as we move our eyes and arms, and process outcomes. High spatiotemporal resolution mapping of multiple cortical areas will improve our understanding of how these neural computations are spatially and temporally distributed across the brain. In this study, we used micro-electrocorticography (µECoG) recordings in two male monkeys performing visually guided reaches to map information related to eye movements, arm movements, and receiving rewards over primary motor cortex, premotor cortex, frontal eye field, and dorsolateral pre-frontal cortex. Time-frequency and decoding analyses revealed that eye and arm movement information shifts across brain regions during a reach, likely reflecting shifts from planning to execution. Although eye and arm movement temporally overlapped, phase clustering analyses enabled us to resolve differences in eye and arm information across brain regions. This analysis revealed that eye and arm information spatially overlapped in motor cortex, which we further confirmed by demonstrating that arm movement decoding performance from motor cortex activity was impacted by task-irrelevant eye movements. Phase clustering analyses also identified reward-related activity in the pre-frontal and premotor cortex. Our results demonstrate µECoG's strengths for functional mapping and provide further detail on the spatial distribution of eye, arm, and reward information processing distributed across frontal cortices during reaching. These insights advance our understanding of the overlapping neural computations underlying coordinated movements and reveal opportunities to leverage these signals to enhance future brain-computer interfaces.Significance statement Picking up your coffee mug requires coordinating movements of your eyes and hand and processing the outcomes of those movements. Mapping how neural activity relates to different functions helps us understand how the brain performs these computations. Many mapping techniques have limited spatial or temporal resolution, restricting our ability to dissect computations that overlap closely in space and time. We used micro-electrocorticography recordings to map neural activity across multiple cortical areas while monkeys made goal-directed reaches. These measurements revealed high spatial and temporal resolution maps of neural activity related to eye, arm, and reward information processing. These maps reveal overlapping neural computations underlying movement and open opportunities to use eye and reward information to improve therapies to restore motor function.

Multiple studies suggest that Parkinson's disease (PD) is associated with changes in neuronal activity throughout the basal ganglia-thalamocortical motor circuit. There are limited electrophysiological data, however, describing how parkinsonism impacts neuronal activity in the pre-supplementary motor area (pre-SMA), an area in the medial frontal cortex involved in movement planning and motor control. In this study, single unit activity was recorded in the pre-SMA of two female non-human primates during a visually cued reaching task in both the naive and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. In the naive state neuronal discharge rates were dynamically modulated prior to the presentation of the instructional go-cue. In a subset of these modulated cells, the magnitude of modulation correlated linearly with reaction time (RT). In the parkinsonian state, however, modulation of discharge rates in the pre-SMA was disrupted and the predictive encoding of RT was significantly diminished. These findings add to our understanding of the role of pre-SMA in motor behavior and suggest that disrupted encoding in this cortical region contributes to the alteration of early preparatory and pre-movement processes present in Parkinson's disease.Significance statement Goal-directed movements, such as reaching for an object, necessitate temporal preparation and organization of information processing within the basal ganglia-thalamocortical motor network. Impaired movement in people with Parkinson's disease is thought to be the result of pathophysiological activity disrupting information flow within this network. This work provides neurophysiological evidence linking altered motor preplanning processes encoded in the neuronal firing pattern of pre-supplementary motor area (pre-SMA) cells to the pathogenesis of motor disturbances in parkinsonism.

Damage to ventromedial prefrontal cortex (vmPFC) in humans disrupts planning abilities in naturalistic settings. However, it is unknown which components of planning are affected in these patients, including selecting the relevant information, simulating future states, or evaluating between these states. To address this question, we leveraged computational paradigms to investigate the role of vmPFC in planning, using the board game task 'Four-in-a-Row' (18 lesion patients, 9 female; 30 healthy control participants, 16 female), and the simpler 'Two-Step' task measuring model-based reasoning (49 lesion patients, 27 female; 20 healthy control participants, 13 female). Damage to vmPFC disrupted performance in Four-in-a-Row compared to both control lesion patients and healthy age-matched controls. We leveraged a computational framework to assess different component processes of planning in Four-in-a-Row and found that impairments following vmPFC damage included shallower planning depth, and a tendency to overlook game-relevant features. In the 'Two-Step' task, which involves binary choices across a short future horizon, we found little evidence of planning in all groups, and no behavioural differences between groups. Complex yet computationally tractable tasks such as 'Four-in-a-row' offer novel opportunities for characterising neuropsychological planning impairments, which in vmPFC patients we find are associated with oversights and reduced planning depth.Significance Statement The ability to plan in real-world settings is often disrupted after damage to ventromedial prefrontal cortex (vmPFC). However, real-world planning consists of many different cognitive processes, and it is uncertain which processes are disturbed by these lesions. Here we use rich computational models of planning to characterise behaviour in two planning tasks performed by patients with vmPFC damage and controls. VmPFC damage only affected behaviour in the more complex planning task, and behavioural modelling revealed this was associated with planning less far into the future and overlooking important features. These findings shed light on the neural mechanisms supporting complex planning, demonstrating how novel computational methods can strike the balance between task complexity and interpretability.

The basic structure of local circuits is highly conserved across the cortex, yet the spatial and temporal properties of population activity differ fundamentally in sensory-level and association-level areas. In sensory cortex, population activity has a shorter timescale and decays sharply over distance, supporting a population code for the fine-scale features of sensory stimuli. In association cortex, population activity has a longer timescale and spreads over wider distances, a code that is suited to holding information in memory and driving behavior. We tested whether these differences in activity dynamics could be explained by differences in network structure. We targeted photostimulations to single excitatory neurons of layer 2/3, while monitoring surrounding population activity using two-photon calcium imaging. Experiments were performed in auditory (AC) and posterior parietal cortex (PPC) within the same mice of both sexes, which also expressed a red fluorophore in somatostatin-expressing interneurons (SOM). In both cortical regions, photostimulations resulted in a spatially restricted zone of positive influence on neurons closely neighboring the targeted neuron, and a more spatially diffuse zone (akin to a network-level 'suppressive surround') of negative influence affecting more distant neurons. However, the relative spatial extents of positive and negative influence were different in AC and PPC. In PPC, the central zone of positive influence was wider, but the negative suppressive surround was more narrow than in AC, which could account for the larger-scale network dynamics in PPC. The more narrow central positive influence zone and wider suppressive surround in AC could serve to sharpen sensory representations.Significance Statement The basic structure of local circuits is highly conserved across the cortex, and yet local processing goals vary across the sensorimotor hierarchy, from sensory perception to the control of behavior. It has been unclear whether these differences in function require different network organization. To probe the spatial structure of networks in sensory and association-level cortex, we photostimulated single excitatory neurons and measured the effect on local population activity in mice. Stimulations triggered a centered, positive activity change in neighboring neurons, and a surrounding, suppressive change in more distant neurons. The relative sizes of the center and surround differed across areas, suggesting that network structure is tailored for sharper, more restricted activity in sensory cortex, and more dense network activity in association cortex.

Prematurely born infants often experience frequent hypoxic episodes due to immaturity of respiratory control resulting in disturbances of cortical development and long-term cognitive and behavioral abnormalities. We hypothesize that neonatal intermittent hypoxia alters maturation of cortical excitatory and inhibitory circuits that can be detected early with functional MRI. C57BL/6 mouse male and female pups were exposed to an intermittent hypoxia (IH) regimen from P3 to P7, corresponding to pre-term humans. Adult mice after neonatal IH exhibited motor hyperactivity and impaired motor learning in complex wheel tests. Patch clamp and evoked field potential recordings revealed increased glutamatergic synaptic transmission. To investigate the role of GABAergic inhibition on glutamatergic transmission during the developmental, we applied a selective GABAA receptor inhibitor picrotoxin. A decreased synaptic inhibitory drive in the motor cortex was evidenced by miniature IPSC frequency on pyramidal cells, multi-unit activity recording in vivo with picrotoxin injection, and decreased interneuron density. There was also an increased tonic depolarizing effect of picrotoxin after IH on Betz cells' membrane potential on patch clamp and direct current potential in extracellular recordings. The amplitude of low-frequency fluctuation on resting-state fMRI was larger, with a larger increase in regional homogeneity index after picrotoxin injection in the IH group.The increased glutamatergic transmission, decreased numbers, and activity of inhibitory interneurons after neonatal IH may affect the maturation of connectivity in cortical networks, resulting in long-term cognitive and behavioral changes. Functional MRI reveals increased intrinsic connectivity in the sensorimotor cortex, suggesting neuronal dysfunction in cortical maturation after neonatal IH.Significance Statement The study demonstrates that perinatal hypoxic brain injury disrupts the balance between excitatory and inhibitory neurotransmission in developing cortical networks. This disruption, potentially caused by functional deficiencies in GABAergic interneurons alongside increased glutamatergic transmission, may contribute to altered brain connectivity and the observed behavioral deficits, including hyperactivity and cognitive difficulties. This research provides insights into how perinatal brain injury disrupts the balance of neural excitation and inhibition, which can be detected as altered local resting-state fMRI connectivity. These findings contribute to our understanding of possible cellular underpinning of clinical fMRI findings after perinatal brain injury.

Deep brain stimulation (DBS) of the ventral capsule and ventral striatum (VC/VS) is an effective therapy for treatment resistant obsessive-compulsive disorder (trOCD). DBS initiation often produces acute improvements in mood and energy. These acute behavioral changes, which we refer to as "approach behaviors", include increased social engagement and talkativeness. We investigated the relationship between stimulation amplitude, spectral power in the ventrolateral prefrontal cortex (vlPFC), and speech rate in one male patient with trOCD implanted with bilateral VC/VS DBS leads and subdural electrodes adjacent to orbitofrontal cortex (OFC) and vlPFC. Several times over the first 17 weeks of therapy, we conducted experiments where we recorded data during epochs of high amplitude or zero/low amplitude stimulation. We found that both speech rate and vlPFC power in a high beta frequency band (31±1.5Hz, 1/f activity removed) increased during high amplitude as compared to low amplitude periods. Speech rate correlated with vlPFC high beta power. These effects were more consistent across time points in the left hemisphere than the right. At week 17, we performed an experiment where stimulation was held constant while the patient was asked to speak or remain silent. We showed that the presence or absence of speech was not sufficient to increase the vlPFC high beta power, suggesting stimulation is a key driver of the observed neurobehavioral phenomenon. Our results suggest vlPFC high beta power is a biomarker for approach behaviors associated with VC/VS DBS.Significance Statement In one patient receiving DBS of the ventral capsule and ventral striatum (VC/VS) for OCD, we leveraged a unique clinical opportunity to study the neurophysiological basis of approach behaviors using chronic intracranial recordings from prefrontal cortical regions. VC/VS DBS initiation often produces acute improvements in mood and energy associated with increased social engagement and talkativeness (approach behaviors). Our results suggest that vlPFC high beta activity (particularly in the left hemisphere) may index approach behaviors (quantified here by speech features). This neural signal is consistent with our previous non-invasive studies identifying predictors of mania in patients with bipolar disorder, and we hope to gather further evidence that it indexes a continuum from adaptive approach behavior to maladaptive manic symptoms.