Journal of Neuroscience最新文献

The small and tortuous volume of synaptic clefts limits the diffusion of Ca²⁺ ions during high frequency spiking. Extracellular Ca²⁺ levels ([Ca²⁺]_o) of 0.8 mM or lower have been measured or calculated for different synapses. Here, we recorded evoked postsynaptic potentials (EPSP) and action potentials (AP) from young adult male and female mouse auditory brainstem principal neurons to investigate the relationship between neurotransmission reliability, stimulation frequency and [Ca²⁺]_o In 0.8 mM [Ca²⁺]_o, we observed AP failures during stimulation at 100 Hz. Surprisingly, AP failures, EPSP-AP latency and jitter were all reduced when stimulation frequency was increased to 500 Hz. Analysis of the EPSP revealed marked facilitation at 500 Hz that was not present at 100 Hz. Raising [Ca²⁺]_o to 1.2 mM or 2.0 mM reduced or eliminated facilitation and, in these conditions that promote EPSP short-term depression, stimulation at 500 Hz increased the number of AP failures. In 0.8 mM Ca²⁺, stimulation over a range of frequencies from 10-1000 Hz produced heterogenous frequency responses. Some principal neurons were unable to evoke fail-safe AP firing during low frequency stimulation (10-100 Hz), but exhibited reliable firing at 300-500 Hz, which was rapid enough to activate EPSP facilitation. At frequencies above 600 Hz, all synapses began to express intermittent transmission failures. We conclude that synaptic facilitation can produce bandpass filtering in firing probability and contribute positively to the maintenance of reliable and precise high frequency neurotransmission in calyx of Held synapses.Significance Statement Facilitation of evoked postsynaptic currents is a common feature of synapses. The strength of facilitation and its role in reaching spike threshold depends on intrinsic properties of the synapse, stimulation frequency, and extracellular Ca²⁺ concentration ([Ca²⁺]_o). Physiological levels of [Ca²⁺]_o can vary from 0.8 to 1.2 mM depending on synaptic activity. In auditory calyx-type synapses, synaptic facilitation is readily observable in brainstem slices using relatively low (0.8 mM) [Ca²⁺]_o, but is partially or completely obscured by short-term synaptic depression when [Ca²⁺]_o is higher (1.2 or 2.0 mM). Here we show that short-term synaptic facilitation can rescue the reliability of high-frequency (500 Hz) action potential firing in low [Ca²⁺]_o.

The nucleus accumbens (NAc) is a critical node in the neural circuitry underlying reward and motivated behavior, including hedonic feeding, and its dysfunction is implicated in maladaptive behaviors in numerous psychiatric disorders. Medium spiny neurons (MSNs) in the NAc are predominantly categorized into dopamine 1 receptor-expressing (D1-MSNs) and dopamine 2 receptor-expressing (D2-MSNs) subtypes, which are thought to exert distinct and sometimes opposing roles in reward-related processes. Here, we used optogenetic, chemogenetic, and fiber photometry approaches in Cre-driver mouse lines to dissect the causal contributions of D1- and D2-MSNs to the consumption of a high-fat diet in sated animals. Activation of D1-MSNs via optogenetics or DREADDs significantly suppressed high-fat intake, whereas inhibition of these neurons increased consumption only in male but not female mice. Conversely, activation of D2-MSNs enhanced high-fat intake only in females, while their inhibition reduced intake in both sexes. Fiber photometry revealed dynamic shifts in D2-MSN activity over repeated high-fat exposures, with increasing activity correlating with escalating intake of high-fat diet only in female mice. These results highlight opposing contributions of D1- and D2-MSN populations in regulating hedonic feeding and support a model in which salience and consumption are modulated by NAc MSN subtype-specific activity in a sex-specific manner. Understanding this circuitry has implications for the development of tailored treatment strategies for obesity and other disorders of compulsive consumption.Significance Statement Obesity and metabolic disorders are partly driven by dysregulated motivation for palatable foods, yet the neural circuits underlying hedonic feeding are not fully understood. This study shows that nucleus accumbens medium spiny neurons have differential, sex-specific roles in high-fat intake: D1-MSN activity suppresses intake in male mice, while D2-MSNs promote consumption in female mice. Using chemogenetics, optogenetics, and fiber photometry, we establish a causal link between MSN activity and hedonic feeding. These findings expand previous models of reward processing and highlight the experience and sex- dependent roles of MSN subtypes. By defining cell-type-specific contributions to non-homeostatic eating, this work offers key insight into the neural basis of hedonic intake and informs strategies for targeted intervention in obesity and related conditions.

The KCND2 gene encodes the Kv4.2 voltage-gated potassium channel alpha subunit that underlies the somatodendritic subthreshold A-type current (I_SA) important for membrane excitability and dendritic signal integration and processing. A heterozygous missense mutation in KCND2 (NM_012281.2: c.1210G>A) was identified in patients with early-onset epilepsy, autism, and global developmental delay, producing a conservative replacement of valine 404 to methionine (Lee et al., 2014; Zhang et al., 2021). To investigate the potential pathological role of the Kv4.2^V404M mutation, we generated Kv4.2^(V404M/+) heterozygous knock-in C57BL/6J mice using CRISPR technology and compared features of development, physiology, and behavior of Kv4.2^(V404M/+) mice to age- and sex-matched wild-type (Kv4.2^(+/+)) littermate controls. Kv4.2^(V404M/+) mice exhibit significant mortality during early development (>50%), poor reproductive behavior, decreased body weight of males (25-30%), altered I_SA functional properties, and 4-5 Hz spike-wave epileptiform discharges. These discharges occur frequently during periods of inactivity, with over 80% occurring during nonrapid eye movement sleep. ΔFosB was found to be significantly elevated in the cortex and hippocampus of Kv4.2^(V404M/+) mice. A combination of home-cage measurements and behavioral assays reveals that Kv4.2^(V404M/+) mice exhibit significant alterations in exploratory behavior, social interaction, fear conditioning, and spatial memory. Our results indicate that the Kv4.2^V404M mutation is sufficient to produce a dominant spectrum of physiological and behavioral changes in mice that likely have important implications for understanding the etiology and potential therapeutic approaches for this human channelopathy.

The multi-factorial pathophysiology of acquired epilepsies lends itself to a multi-targeting therapeutic approach. MicroRNAs (miRNA) are short noncoding RNAs that individually can negatively regulate dozens of protein-coding transcripts. Previously, we reported that central injection of antisense oligonucleotides targeting microRNA-134 (Ant-134) shortly after status epilepticus potently suppressed the development of recurrent spontaneous seizures in rodent models of temporal lobe epilepsy. The mechanism(s) of these anti-seizure effects remain, however, incompletely understood. Here we show that intracerebroventricular microinjection of Ant-134 in male mice with pre-existing epilepsy caused by intraamygdala kainic acid-induced status epilepticus potently reduces the occurrence of spontaneous seizures. Recordings from ex vivo brain slices collected 2-4 days after Ant-134 injection in epileptic mice, detected a number of electrophysiological phenotypic changes consistent with reduced excitability. Specifically, Ant-134 reduced action potential bursts after current injection in CA1 neurons and reduced excitatory post-synaptic current frequencies in CA1 neurons. Ant-134 also reduced general network excitability, including attenuating pro-excitatory CA1 responses to Schaffer collateral stimulation in hippocampal slices from epileptic mice. Together, the present study demonstrates inhibiting miR-134 reduces single neuron and network hyperexcitability in mice and extends support for this approach to treat drug-resistant epilepsies.Significance statement Temporal lobe epilepsy is one of the most common forms of drug-resistant epilepsy. Identifying molecular regulators of enduring states of hyperexcitability may lead to new therapeutic approaches. MicroRNAs are short noncoding RNAs that act post-transcriptionally to lower levels of sets of protein-coding genes. Here we show that inhibiting miR-134 reduces spontaneous seizures in mice with active epilepsy. Electrophysiologic recordings from brain slices collected when mice were transitioning to fewer seizures revealed changes to both single neuron and inter-regional communication properties that may explain the reduction in hippocampal network excitability. The findings support the development of this microRNA-targeting approach for epilepsy.

Mathematical learning disabilities (MLD) affect up to 14% of school-age children, yet the underlying neurocognitive mechanisms remain elusive. We developed Drift Diffusion Model with Dynamic Performance Monitoring (DDM-DPM), an innovative cognitive model that captures both external and internal sources of structural variability in task performance. Combining DDM-DPM with functional brain imaging, we examined symbolic and non-symbolic quantity discrimination in female and male children with MLD and typically developing children matched on age, gender, and IQ. Children with MLD showed format-dependent alterations in response caution and post-error adjustment, despite similar observed performance measures between groups. The latent cognitive processes during symbolic quantity discrimination predicted broader mathematical abilities better than those during non-symbolic quantity discrimination. Neuroimaging results revealed that reduced activity in middle frontal gyrus mediated deficits in response caution in symbolic format, while reduced activity in the anterior cingulate cortex mediated deficits in post-error adjustment in symbolic format in children with MLD. These findings provide novel support for a multidimensional deficit view of MLD that extends beyond basic number processing to include metacognitive processes. Our findings also provide novel support for and extend the access deficit model, which posits that individuals with MLD may have relatively intact quantity representations but struggle with numerical representations in symbolic formats. Our study highlights the value of integrating latent cognitive modeling with neuroimaging to reveal subtle mechanisms underlying learning disabilities and identify potential targets for intervention.Significance Statement Considerable debate exists regarding the nature of deficits in mathematical learning disabilities (MLD). By developing an innovative computational model that captures subtle aspects of decision-making processes, we reveal that children with MLD show specific difficulties in adapting their problem-solving strategies when working with numerical symbols. Using brain imaging, we found that these difficulties are linked to reduced activity in brain regions involved in monitoring and adjusting behavior. Importantly, these deficits were specific to symbolic number processing and predicted children's broader mathematical abilities. Our findings suggest that MLD involves not only difficulties with basic number processing, but also problems in regulating cognitive strategies when working with numerical symbols. This insight could lead to more effective interventions for children struggling with mathematics.

Our ability to retrieve the names of objects in our environment is a fundamental aspect of everyday life. This process requires a complex, dynamic network of cortical and subcortical interactions. While the cortical constituents of this network have been extensively studied with intracranial recordings, the subcortical nodes of the naming network are unclear. We probed the role of the left medial pulvinar nucleus in naming with direct intracranial recordings and stimulation in eight humans (3 male, 5 female) as they named objects using pictures, and auditory and written descriptions. We found a spectrotemporal signature of naming in the left medial pulvinar nucleus, characterized by a low frequency (8-20Hz) suppression, consistent across sensory modalities during naming, and absent during other non-naming language tasks. Within this frequency band, Granger causal interactions showed that the pulvinar nucleus received strong inputs from early visual, ventral temporal, and parahippocampal cortices. Direct thalamic stimulation reliably induced anomia, confirming that the left medial pulvinar nucleus is a critical node in the distributed naming network.Significance Statement for most people, the ability to retrieve the names of objects is a rapid, effortless process. However, damage to the brain's naming network can disrupt this ability. While the cortical hubs of the naming network have been extensively documented, the contributions of subcortical regions to naming are unclear. We used the rare opportunity to record directly from one such subcortical region, the medial pulvinar nucleus, in patients who were having electrodes placed for the treatment of epilepsy, to characterise its role in naming. Based on its neural activation, functional connectivity with cortical naming hubs, and causal role in behaviour when disrupted, this work provides direct evidence of the critical role of pulvinar in naming.

Parkinson's disease is a late onset neurodegenerative disease characterized by preferential degeneration of midbrain dopaminergic neurons and α-synuclein containing Lewy bodies that are found in both familial and sporadic forms. Genome wide association studies (GWAS) have identified many loci associated with risk of sporadic PD, but their role in PD pathogenesis remains largely unknown. We screened a subset of GWAS genes in Caenorhabditis elegans (C.elegans) as potential modulators of α-synuclein-mediated degeneration of dopaminergic neurons. Loss of ari-2 (human ARIH2), an E3 ubiquitin ligase was identified as the strongest suppressor of dopaminergic neurodegeneration in C.elegans. Unbiased proteomics analysis in human iPSC-derived dopaminergic neurons revealed novel substrates of ARIH2 including TPPP3, a regulator of microtubule dynamics. Importantly, TPPP3 was required for ARIH2's effects on α-synuclein induced dopaminergic neurodegeneration. Our studies reveal an unexpected genetic interaction between two PD-linked genes α-synuclein and ARIH2, and suggest that inhibition of ARIH2's enzymatic activity may serve as a potential therapeutic approach in PD.Significance Statement Parkinson's disease (PD) is a devastating neurodegenerative disorder marked by α-synuclein accumulation. Genome wide association studies (GWAS) have identified multiple risk genes linked to PD but their functional roles and crosstalk with α-synuclein are not completely understood. Here, we screened multiple GWAS-linked genes using an in vivo α-synuclein model of PD. We discovered that loss of αri-2 (human ARIH2), an E3 ubiquitin ligase was the strongest suppressor of dopaminergic neuron loss, and identified substrates of ARIH2 in human dopaminergic neurons which mediate this pathway. This work reveals a genetic interaction between two PD linked genes, ARIH2 and α-synuclein and provides important insights into neurodegeneration in PD.

Flexible prioritisation in working memory (WM) is supported by neural oscillations in frontal and sensory brain areas, but the roles of different oscillations remain poorly understood. Recordings in humans suggest an interplay between prefrontal slow frequency (2-8Hz) and posterior alpha-band (10Hz) oscillations regulating top-down control and retrieval of WM representations, respectively. Complementary work, primarily in non-human primates, suggests an additional role for beta (15-30Hz) oscillations in clearing or inhibiting stimuli from entering WM. Here we investigated the role of neural oscillations in prioritising WM content using electroencephalography (EEG) as participants (humans of any sex) performed a task requiring frequent priority switches between two memorized oriented bars. Behavioural performance revealed switch costs, which scaled with the angular distance between the two items, suggesting that priority shifts are modulated by shift magnitude. Time-frequency analyses revealed increased frontal theta (4-8Hz) and decreased central-parietal beta (15-25Hz) power during switches. Crucially, only beta power scaled with the magnitude of the priority shift and predicted the fidelity of neural decoding of the newly prioritized item during subsequent recall. Theta power, by contrast, was elevated on switch trials but did not vary with update magnitude or decoding strength, suggesting a more general role in signaling control demands. Our findings highlight a particular and previously overlooked role for beta-band oscillations in the flexible prioritisation of WM content.Significance Statement Working memory permits flexible switching between mental representations, so we can focus on what is most relevant at the moment. Different brain rhythms in frontal control and sensory memory storage areas orchestrate switches but their respective roles remain unclear. Here, using EEG, we show that power reductions of ∼20Hz oscillations over central-parietal regions, usually associated with the motor system, closely track the magnitude of the required switch and the fidelity of the prioritized memory. In contrast, slower 4-8Hz (theta-band) activity over frontal regions increases during priority switches but tracks neither magnitude nor fidelity. Our findings suggest a unique function for central-parietal beta oscillations in the flexible control of working memory.

Higher order (HO) thalamic nuclei are characterized by receiving driver input from layer 5 (L5) of cortex and serve as a transthalamic route of corticocortical communication. These HO nuclei are also innervated by subcortical sources. In the posterior medial nucleus (POm), a somatosensory HO thalamic nucleus, excitatory glutamatergic inputs arise from L5 of sensorimotor cortices and the spinal trigeminal nucleus (SpV), while inhibitory GABAergic sources are the anterior pretectal nucleus (APn) and zona incerta (ZI). Here, we tested a key postulate of transthalamic pathway function: that their disynaptic nature allows information traversing them from L5 to be modulated or gated by other inputs. We used optogenetics in acute slices from mice (both sexes) to test individual POm relays for convergent innervation. We found that modulatory inputs from SpV intersect with drivers from L5 of somatosensory cortex. Further, GABAergic inputs from the APn converge with both L5 and SpV inputs. In contrast, we found minimal convergence between ZI and L5 or SpV-a surprise considering previous evidence that ZI blocks whisker-dependent activation of POm relays. Therefore, we sought alternative explanations for this discrepancy. First, we detected robust convergence in POm between the ZI (and APn) and superior colliculus, which is whisker responsive. Second, we discovered that ZI innervates the thalamic reticular nucleus with glutamatergic synapses, comprising an alternative feedforward inhibitory circuit to POm. These results substantiate several mechanisms by which transthalamic information is modulated or gated while enhancing the resolution of our understanding of POm function.Significance Statement Environmental information arrives in cortex via pathways relayed through thalamus. It is then further processed by at least two circuits: direct corticocortical connections and recently appreciated cortico-thalamo-cortical (transthalamic) circuits. But why have transthalamic pathways that parallel direct ones? Here, we provide evidence for a potential reason-information traversing transthalamic circuits can be modified by inputs that converge onto transthalamic relay cells. Indeed, we show that both excitatory modification and inhibitory gating of transthalamic signals, as well as signals to thalamus relayed from certain subcortical sources, occur on relay cells in the somatosensory thalamus. These findings set the stage for understanding how individual thalamic relays integrate bottom-up and top-down (i.e., corticothalamic) information to dynamically regulate interregional cortical communication.

Knowledge of how vocal communication signals are represented in the auditory system is crucial for understanding the perceptual basis of vocal communication. Using male and female zebra finches, we identified a series of differentially expressed markers that helped define distinct (caudal, rostral, dorsal and ventral) domains within the caudomedial nidopallium (NCM), a high-order cortical auditory area known for its song-selective responses. Using expression analysis of the activity-inducible gene zenk, we found that the number of activated neurons is more stimulus dependent in NCM than in the auditory midbrain or the caudomedial mesopallium, and that information on the density and spatial distribution of responsive neurons in NCM is sufficient to discriminate responses to conspecific song from other stimuli. We observed stronger activation of dorsal NCM, higher selectivity of caudal NCM towards conspecific song, and strong activation of the inhibitory network of rostral NCM by non-conspecific song stimuli. Song auditory representation in NCM was dependent on acoustic features, with the spatial organization of responsive cells particularly sensitive to both spectral and temporal components. We also obtained evidence of broadly distributed song-selective neuronal ensembles and that individual NCM neurons participate in the representation of conspecific songs, implying independent activation and molecular induction responses. We conclude that some basic aspects of the cortical response to complex auditory stimuli are topographically organized, a finding that has been elusive in other systems. These findings advance our knowledge of the functional organization of a key song-processing cortical area, providing novel insights into the auditory representation of conspecific vocal communication signals.Significance Statement Understanding how vocal signals are processed and represented in the brain is fundamental to the study of animal communication. Songbirds provide a powerful model for investigating these processes due to their rich vocal behavior and well-characterized neural circuits. Through analysis of differentially expressed markers and mapping of activity-induced gene expression, we have uncovered how different domains and neuronal populations within a high-order auditory cortical area respond to acoustic features of song and other stimuli. Besides providing in-depth knowledge of the functional organization of a key avian brain area, these findings provide insights into how acoustic features of complex learned vocal signals are processed and represented in cortical circuits, including evidence of how basic aspects of this representation can be topographically organized.