Journal of Neuroscience最新文献

Autosomal dominant mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), underlie spinocerebellar ataxia type 27A (SCA27A), a devastating multisystem disorder resulting in progressive deficits in motor coordination and cognitive function. Mice lacking iFGF14 exhibit similar phenotypes, which have been linked to iFGF14-mediated modulation of the voltage-gated sodium (Nav) channels that regulate high-frequency repetitive firing of cerebellar Purkinje neurons, the main output neurons of the cerebellar cortex. To investigate the in vivo mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus (Fgf14^F145S ). Current-clamp recordings from Purkinje neurons in acute cerebellar slices from adult male and female Fgf14^F145S/+ mice revealed that high-frequency repetitive firing, which is characteristic of wild-type Purkinje neurons, was replaced by prolonged bursts of action potentials. A shift from tonic to burst firing was mimicked in wild-type Purkinje neurons by bath application of the Nav channel toxin, tetrodotoxin. Burst firing was also measured in heterozygous Fgf14 knock-out (Fgf14^+/- ) Purkinje neurons, suggesting that the impaired firing of Fgf14^F145S/+ Purkinje neurons reflects reduced Nav channel availability, owing to the loss of the iFGF14 protein. Western blot analyses confirmed reduced iFGF14 protein expression in cerebellar lysates prepared from Fgf14^F145S/+ (and Fgf14^+/- ) animals and voltage-clamp experiments revealed a hyperpolarizing shift in the voltage dependence of closed-state Nav channel inactivation in Fgf14^F145S/+ (and Fgf14^+/- ) Purkinje neurons. Together, these results indicate that Fgf14 haploinsufficiency and reduced Nav channel availability underlie impaired firing in Fgf14^F145S/+ Purkinje neurons.

The basal ganglia play a key role in visual perceptual decisions. Despite being the primary target in the basal ganglia for inputs from the visual cortex, the posterior striatum's (PS) involvement in visual perceptual behavior remains unknown in rodents. We reveal that the PS direct pathway is largely segregated from the dorsomedial striatum (DMS) direct pathway, the other major striatal target for the visual cortex. We investigated the role of the PS in visual perceptual decisions by optogenetically stimulating striatal medium spiny neurons in the direct pathway (D1-MSNs) of male and female mice performing a visual change-detection task. PS D1-MSN activation robustly biased visual decisions in a manner dependent on visual context, timing, and reward expectation. We examined the effects of PS and DMS direct pathway activation on neuronal activity in the superior colliculus (SC), a major output target of the basal ganglia. Activation of either direct pathway rapidly modulated SC neurons but mostly targeted different SC neurons and had opposite effects. These results demonstrate that the PS in rodents provides an important route for controlling visual decisions, in parallel with the better-known DMS and with distinct anatomical and functional properties.

Selective attention is the collection of mechanisms through which the brain preferentially processes behaviorally important information. Many everyday tasks, such as shopping for groceries, require selective sampling (i.e., attention-related sampling) of both external information (i.e., information from the environment) and internally stored information (i.e., information being maintained in working memory). While there is clear evidence that selective sampling of external information is influenced by internally stored information (and vice versa), the extent to which selective sampling of external and internal information compete for the same neural resources and attention-related processes remains a focus of debate. Previous research has linked theta-rhythmic (3-8 Hz) neural activity in higher-order (e.g., frontal cortices) and sensory regions to theta-rhythmic changes in behavioral performance during selective sampling. Here, we used EEG and a dual-task design (i.e., a task that required both external and internal information), in male and female humans, to directly compare theta-dependent fluctuations in behavioral performance during external sampling with those during internal sampling. Our findings are consistent with a shared theta-rhythmic process for selectively sampling external information or internal information. This theta-rhythmic sampling is associated with both phase-dependent changes in sensory responses (i.e., as measured with the N1 component) and phase-dependent changes in interactions between external and internal information. The theta phase associated with weaker sensory responses and relatively worse behavioral performance (i.e., the 'bad' phase) is also associated with a slowed perceptual decision-making process (as measured with the CPP component), specifically during dual-task trials when to-be-detected external information matches to-be-remembered internal information.Significance statement Most everyday tasks require information from both the external environment and internal memory stores; however, the extent to which selective processing of external and internal information rely on shared neural mechanisms and resources remains a subject of debate. Recent work has demonstrated attention-related, theta-rhythmic fluctuations (3-8 Hz) in neural activity and behavioral performance, perhaps reflecting the temporal coordination of competing functions (e.g., attention-related sampling and shifting). Here, we used EEG and a dual-task design to provide evidence of a shared, theta-rhythmic process for alternately boosting the sampling of either external or internal information. This shared, theta-rhythmic process also modulates interactions between external and internal information on dual-task trials, when these sources of information compete for limited processing resources.

In the mammalian cochlea upon acoustic stimulation, outer hair cells (OHCs) push and pull the basilar membrane, amplifying its vibration and therefore expanding the dynamic range of hearing. As a result, spiking patterns in auditory nerve fibers (ANFs) are believed to be significantly different, but how the central nervous system adapts to this substantial change is poorly understood. In this study, we took advantage of Prestin^-/- mice of either sex where prestin, the motor protein in OHCs, was genetically knocked out, therefore removing cochlear amplification completely without changing the cellular structure of the cochlea significantly. While exocytosis from inner hair cells in the cochlea was largely intact, transmission at the endbulb of Held synapse between ANFs and bushy cells in the cochlear nucleus was significantly changed in Prestin^-/- mice. Specifically, excitability of bushy cells was significantly increased, due to combination of slightly more depolarized resting membrane potential, increased membrane input resistance, and smaller and briefer after-hyperpolarization. Furthermore, synaptic strength was greatly reduced, caused by substantial decrease in the readily releasable pool (RRP) of synaptic vesicles. Significantly, paired-pulse plasticity at this synapse was reversed from depression in WT mice to facilitation in Prestin^-/- mice, likely caused by quicker refilling of RRP observed in Prestin^-/- mice. In conclusion, we found that transmission at the endbulb of Held synapse is significantly altered in absence of cochlear amplification, revealing interplay between the peripheral and central processing of auditory signals that contributes to expanded dynamic range of hearing seen in mammals and humans.Significance Statement The mammalian cochlea is an amazing sensory apparatus with remarkable sensitivity, largely owning to cochlear amplification that is estimated to be ∼1,000 folds. As a result, auditory nerve fibers are expected to fire spikes with significantly different patterns. If and how central circuits adapt to this substantial change of cochlear input are poorly understood. To address this fundamental question, we abolished cochlear amplification in Prestin^-/- mice and examined functional changes in the cochlear nucleus. We found that excitability of bushy cells was increased, and transmission at the endbulb of Held synapse was significantly altered. We therefore revealed an active interaction between the hearing organ and central circuits that expands our understanding of hearing in general.

In Alzheimer's disease (AD) models, ventral tegmental area (VTA) dopamine neurons are intrinsically hyperexcitable, yet release less dopamine and exhibit dysfunctional downstream signaling. Synaptic transmission is broadly disrupted in AD, but it is not known to what extent excitatory and inhibitory inputs to the VTA are altered. Here we describe enhanced synaptic excitation in dopamine neurons from male and female 3xTg-AD mice (an amyloid + tau-driven model). AMPAR-mediated excitatory input was enhanced in a subset of connections, while GABA_AR-mediated inhibition decreased as a function of dendritic atrophy. Protein phosphorylation analysis and pharmacology suggested that strengthened excitation depends on both presynaptic protein kinase C activity and postsynaptic enhancement of perisomatic AMPA receptor currents. Biophysical modeling predicted that enhanced excitatory synaptic input in 3xTg-AD dopamine neurons, combined with altered dendritic morphology and intrinsic hypersensitivity, produces increased firing and a steeper input-output relationship. These results suggest that AD pathology is associated with increased sensitivity of single dopamine neurons, which may serve to maintain phasic dopamine signaling in early stages of degeneration.Significance Statement While recent studies describe a suspected role for VTA dopamine neurons in Alzheimer's disease, the influence of excitatory and inhibitory input as well as single neuron morphology is not known. Using single-cell patch-clamp electrophysiology we find that 3xTg-AD dopamine neurons receive enhanced glutamatergic synaptic input and reduced inhibitory GABA input, thus tipping the balance further toward excitation. By combining this with morphological reconstructions, multicompartmental biophysical modeling, and past findings of intrinsic hypersensitivity, we predict that synaptic changes drive increased burst firing and convey a steeper input-output relationship in 3xTg neurons. These modifications likely alter downstream signaling or serve as a compensatory protective mechanism in the face of degenerative pathology in AD.

Communication from secondary (M2, premotor) to primary (M1) motor cortex is implicated in forelimb motor control. We investigated the underlying synaptic circuits in this corticocortical pathway in male and female mice using cell-type-specific optogenetic-electrophysiology methods, focusing on identifying the cell-type-specific synaptic connections in the excitatory and feedforward inhibitory circuits impinging on cervically projecting M1 corticospinal neurons. In forelimb M1 brain slices, recordings from layer 5B corticospinal neurons during brief photostimulation of M2 axons showed strong monosynaptic excitatory currents that, although accompanied by potent feedforward inhibitory currents, were capable of evoking action potentials (APs) in most neurons. In contrast, responses in layer 2/3 pyramidal neurons were generally much weaker. Parvalbumin-expressing neurons (PV), particularly in deeper layers, showed direct excitation from M2 axons without feedforward inhibition, and could fire APs robustly. Somatostatin (SST) neurons received generally weak inputs, whereas VIP and Ndnf neurons received stronger excitation and inhibition from M2 axons. Corticospinal neurons received little or no local inhibition from Ndnf and VIP interneurons, but relatively strong soma-targeting PV and dendrite-targeting SST inhibitory inputs, as functionally imaged by laser-scanning synaptic input mapping ("sCRACM"). The domains of PV and SST inputs were partly overlapping around the corticospinal somata, but broader for PV and more vertical for SST inputs. Collectively, the results provide a working model for the cell-type-specific synaptic circuits of this "top-down" corticocortical pathway, organized around direct M2 excitation and PV-mediated inhibition of M1 corticospinal neurons.Significance statement Cervically projecting corticospinal neurons in the primary motor cortex (M1) serve as the most direct conduits by which motor cortical activity reaches and influences spinal circuits controlling forelimb movements. Corticospinal activity is in turn influenced by inputs from multiple upstream areas. Here we studied the inputs from the secondary motor cortex (M2), a premotor-like area in the mouse, and characterized the patterns of synaptic connectivity formed by M2 axons onto multiple postsynaptic cell types in M1. The resulting "wiring diagram" suggests that these inter-areal circuits are configured to give premotor cortex privileged access to modulate M1 corticospinal output, through cell-type-specific connections and inhibitory mechanisms.

Sudden environmental changes can render planned hand movements suboptimal or even counterproductive. To prevent the execution of outdated motor plans, the motor system may transiently inhibit actions following salient changes, allowing time to evaluate alternatives. While such a mechanism is well-established for eye movements, its applicability to hand movements remains unclear. Here, we present findings from three online behavioral experiments and two lab-based replications designed to probe key features of this mechanism in manual responses: reflexive inhibition, temporal precedence, complete movement updating, and sensitivity to saliency. Participants of either sex performed rapid sequential tapping movements toward onscreen targets. At an unpredictable time, either a relevant change (a target displacement) or an irrelevant change (a brief luminance flash) occurred. We measured movement initiation rates following these changes and compared them to a no-change baseline. A significant transient inhibition of movement initiation followed both relevant and irrelevant changes. This inhibition preceded observable updates to the movement plan. At the time of inhibition release, the update to a movement plan was complete. Across experiments, we observed stronger inhibitory effects for more salient changes. The lab-based replication confirmed that the latency of this inhibitory response aligns with visuomotor reaction times. These results support the existence of a general-purpose, rapid inhibitory mechanism in hand movements analogous to inhibition in the oculomotor system. We propose that such inhibition provides a reflexive, domain-general safeguard against obsolete actions following unexpected changes.Significance Statement As we act within dynamic environments, sudden changes can invalidate our planned movements. In such cases, rather than relying on continuous sensorimotor integration, the brain may employ a different mechanism: the rapid inhibition of potentially outdated actions. Our studies show that the human motor system exhibits abrupt, non-selective inhibition in response to unexpected changes. This response occurs before the selection of a new action, suggesting a central, preemptive control process. These findings highlight an automatic, stimulus-driven mechanism that interrupts ongoing motor activity. This work advances our understanding of how the brain prioritizes error prevention over movement execution in action planning, with implications for models of sensorimotor control.

Rewards signal information in the environment that is valuable and thus useful to remember. Rewards benefit memory across development, but how reward-associated memories are represented in the brain has not been well characterized. Here we conducted pattern similarity analyses of fMRI data in male and female participants aged 8-25 to elucidate how neural representations in key memory-related brain areas are influenced by reward, and how these relationships change across childhood and adolescence. We found that reward information was reflected in pattern similarity during encoding in ventral temporal cortex and in changes in similarity from encoding to retrieval in anterior hippocampus (aHC). Strikingly, aHC reward-sensitive representations also varied with age such that adults' memory benefitted from stability of hippocampal representations, whereas younger participants' memory improvements were associated with greater drift in representations over time. Moreover, across all participants, reward-related univariate activation in the ventral tegmental area was associated with a greater tendency toward representational drift in aHC. Taken together, our findings demonstrate that reward modulates neural memory representations, and that the representational patterns supporting reward-motivated memory shift with age.Significance statement Rewards benefit memory across development, but how these memories are represented in the brain has not been well characterized. Here we looked at multivariate patterns of brain activity in children, adolescents, and adults and found that the reward level (high versus low) assigned to pairs of pictures influenced participants' neural patterns both during learning and when they retrieved the pairs from memory. Strikingly, in the hippocampus, adults' memory for high-reward pairs benefitted from pattern stability over time, while children and adolescents' high-reward memory benefits were associated with greater change in hippocampal patterns from encoding to retrieval. These results demonstrate that neural representations of reward-associated memories change with age across development.

Neuronal oscillations are a ubiquitous feature of thalamocortical networks and can be dynamically modulated across processing states, enabling thalamocortical communication to flexibly adapt to varying environmental and behavioral demands. The lateral geniculate nucleus (LGN), like all thalamic nuclei, engages in reciprocal synaptic interactions with the cortex, relaying retinal information to and receiving feedback input from primary visual cortex (V1). While retinal excitation is the primary driver of LGN activity, retinal synapses represent a minority of the total synaptic input onto LGN neurons, allowing for both retinogeniculate and geniculocortical signals to be influenced by nonretinal sources. To gain a holistic view of network processing in the geniculocortical pathway, we performed simultaneous extracellular recordings from the LGN and V1 of behaving macaque monkeys (two male, four female), measuring local field potentials (LFPs) and spiking activity. These recordings revealed prominent beta-band oscillations coherent between the LGN and V1 that influenced spike timing in the LGN and were statistically consistent with a feedforward process from the LGN to V1. These thalamocortical oscillations were suppressed by visual stimulation, spatial attention, and behavioral arousal, strongly suggesting that these oscillations are not a feature of active visual processing. Instead, they appear analogous to occipital lobe, alpha oscillations recorded in humans and may represent a signature of signal suppression that occurs during periods of low engagement or active distractor suppression.Significance Statement Oscillations within thalamocortical networks in the awake state are generally believed to enhance communication between the thalamus and cortex, allowing circuits to flexibly respond to changes in sensory, behavioral, and cognitive demands. Here, we show that oscillations within and between the LGN and V1 are suppressed by increases in visual stimulation, increases in behavioral arousal, and shifts in covert spatial attention. We therefore conclude that these oscillations are not a mechanism to enhance the transmission of retinal information through the LGN to V1. Instead, we propose that they are a signature of signal suppression that occurs when network engagement is low or during active distractor suppression.

The past two decades have seen increased interest in the function of dopamine (DA) by virtue of its role in generating Reward-Prediction Errors (RPEs) in the service of Reinforcement Learning. From the perspective of systems neuroscience, most of this research has focused on the mesostriatal and mesoaccumbens DA pathways, as technical limitations have prevented a detailed examination of the role of RPEs in the medial frontal cortex (MFC). The recent development of DA-sensitive fluorescent sensors and fiber photometry now provides relatively selective measures of DA responses, with high temporal resolution. Here the technique was used to compare MFC DA responses to appetitive, aversive, and neutral events, along with violations in learned contingencies that should theoretically generate robust RPEs in male rats. Aversive and rewarding outcomes evoked DA responses of comparable magnitude, although responses to tones paired with footshock evoked larger responses than those paired with food. Conditions used successfully to create RPEs in striatum, such as omitting outcomes, failed to provide clear evidence of signed RPE-like DA responses in the MFC. Furthermore, DA responses were similar in magnitude regardless of whether outcomes were expected or unexpected/swapped. The most parsimonious conclusion from these experiments would be that while the MFC DA is capable of conveying weak RPEs, it mainly tracks the physiological arousal created by the affective properties of appetitive or aversive stimuli.