Journal of Neuroscience最新文献

The central nervous system is characterized by its limited regenerative potential, yet striking examples of functional recovery after injury in animal models and humans highlight its capacity for repair. Little is known about repair of pathways/circuits after traumatic brain injury (TBI), which results in disruption of connectivity. Here we utilize a mouse model of diffuse traumatic axonal injury (impact-acceleration TBI) in order to explore, for the first time, the evolution of structural and functional changes in the terminal fields of the injured visual system. Retinal ganglion cell (RGC) axons and synapses were genetically labeled via AAV transduction, while anterograde and transsynaptic tracers were used to mark terminals and postsynaptic cells. Functional connectivity and visual integrity were assessed by monitoring c-Fos expression following light stimulation and pattern-reversal visual evoked potentials (pVEPs). Our findings demonstrate that, although TAI results in an ∼50% loss of RGC axons and terminals, surviving RGCs undergo collateral sprouting, a form of compensatory branching of surviving axons, that restores terminal density to preinjury levels. Transsynaptic tracing and c-Fos mapping confirmed the reestablishment of connectivity, which was also associated with significant improvements in visual function as measured by pVEPs. Interestingly, the recovery process exhibited sexual dimorphism, with female mice showing delayed or incomplete repair. Moreover, collateral sprouting proceeded normally in Sarm1 knock-out mice, evidence of some independence from Wallerian degeneration. Our findings show that collateral sprouting may be an important mechanism of circuit repair in TAI and may represent a promising target for therapeutic interventions.

Working memory (WM) capacity has been claimed to be larger for meaningful objects than for simple features, possibly because richer semantic representations enhance item distinctiveness. However, prior demonstrations compared trial-unique meaningful objects with a small set of repeated simple features. This design confounds meaningfulness with proactive interference (PI), such that PI is minimal for trial-unique objects but substantial for repeated features. Therefore, superior performance for meaningful objects may reflect contributions from episodic long-term memory (LTM) rather than expanded WM capacity. To test this, Experiment 1 measured WM for repeated colors, repeated meaningful objects, and trial-unique meaningful objects from 31 human observers (18 females). The advantage for objects over colors was replicated in the trial-unique condition but eliminated for repeated objects that equated PI across stimulus types. Hierarchical Bayesian dual-process modeling revealed that this advantage reflected stronger familiarity signals, whereas recollection remained stable across stimulus types. Experiment 2 assessed WM storage directly using contralateral delay activity (CDA), an electrophysiological marker of the number of items stored, from 25 observers (14 females). Although trial-unique objects again yielded behavioral advantages, CDA activity across increasing set sizes revealed a common slope and plateau for trial-unique meaningful objects and repeated colors. The CDA difference between stimulus types was additive and did not vary with the set size, providing no evidence for increased WM storage. These findings suggest that object advantages in WM reflect reduced PI and enhanced contributions from LTM. When PI is equated, WM storage limits for simple and meaningful stimuli are equivalent.

Visual selective attention is not wired into the brain fully formed and immutable but is acquired and refined as animals learn by interacting with their environment. Here we investigated this process by studying neuronal activity in the superior colliculus (SC) of male and female mice that learned different meanings of the same visual stimuli. We recorded spiking activity of neurons across the superficial and deep SC layers in three cohorts of mice, each trained using a tailored set of task rules that attributed different levels of behavioral relevance to the visual stimuli. Experimental conditions across the three tasks were carefully matched for visual stimulation and task engagement. We found that several markers of attention-related activity depended on the level of learned behavioral relevance, with the strongest effects in deep SC. First, for activity evoked by cue onset, visual responses in superficial SC were larger in animals that exhibited higher learned relevance. In deep SC, the presence of visual onset responses depended entirely on the learned behavioral relevance. Second, traditional attention-related modulation, defined as enhanced steady-state activity for the visual stimulus at the cued location, was also stronger with higher learned relevance, and this effect was limited to deep SC. Finally, the response to the visual change at the cued location was virtually absent when learned behavioral relevance was low but was prominent after visual training. Together, these results reveal that several fundamental features of attention-related modulation depend on the behavioral relevance learned through task-specific training, including aspects of stimulus-driven attention.

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.