Hyperglycemia is a comorbidity in 60–80% of stroke patients; nevertheless, neuroprotective drugs like NMDA receptor (NMDAR) antagonists are typically assessed in normoglycemic animals at the preclinical stage before they are approved to enter clinical trials. Interestingly, as a possible explanation for the translational failure of NMDAR antagonists, it was recently reported that stroke occurring during nighttime causes smaller infarctions in rodents and therefore has a smaller window for neuroprotection. To investigate why stroke occurring during different circadian phases confers a difference in severity, we reanalyzed the published source data and found that some mice that were used in the daytime have higher blood glucose than mice that were used in the nighttime. We then repeated the experiments but found no difference in blood glucose concentration or infarct volume regardless of the circadian phase during which stroke occurs. On the other hand, induction of hyperglycemia by glucose injection reprodu...

Multisensory plasticity enables our senses to dynamically adapt to each other and the external environment, a fundamental operation that our brain performs continuously. We searched for neural correlates of adult multisensory plasticity in the dorsal medial superior temporal area (MSTd) and the ventral intraparietal area (VIP) in two male rhesus macaques using a paradigm of supervised calibration. We report little plasticity in neural responses in the relatively low-level multisensory cortical area MSTd. In contrast, neural correlates of plasticity are found in higher level multisensory VIP, an area with strong decision-related activity. Accordingly, we observed systematic shifts of VIP tuning curves, which were reflected in the choice-related component of the population response. This is the first demonstration of neuronal calibration, together with behavioral calibration, in single sessions. These results lay the foundation for understanding multisensory neural plasticity, applicable broadly to maintaini...

Tracking and quantifying the abundance and location of cells in the developing brain is essential in neuroscience research, enabling a greater understanding of mechanisms underlying nervous system morphogenesis. Widely used experimental methods to quantify cells labeled with fluorescent markers—such as immunohistochemistry, in situ hybridization, and expression of transgenes via stable lines or transient in utero electroporations—depend upon accurate and consistent quantification of images. Current methods to quantify fluorescently-labeled cells rely on labor-intensive manual counting approaches, such as the Fiji plugin Cell Counter , which requires custom macros to enable higher-throughput analyses. Here, we present RapID Cell Counter, a semi-automated cell-counting tool with an easy-to-implement graphical user interface, that facilitates quick and consistent quantifications of cell density within user-defined boundaries that can be divided into equally-partitioned segments. Compared to the standard manua...

With the wide adoption of genomic sequencing in children having seizures, an increasing number of SCN2A genetic variants have been revealed as genetic causes of epilepsy. Voltage-gated sodium channel Nav1.2, encoded by gene SCN2A , is predominantly expressed in the pyramidal excitatory neurons and supports action potential firing. One recurrent SCN2A genetic variant is L1342P, which was identified in multiple patients with epileptic encephalopathy and intractable seizures. However, the mechanism underlying L1342P-mediated seizures and the pharmacogenetics of this variant in human neurons remain unknown. To understand the core phenotypes of the L1342P variant in human neurons, we took advantage of a reference human induced pluripotent stem cell (hiPSC) line from a male donor, in which L1342P was introduced by CRISPR/Cas9 mediated genome editing. Using patch-clamping and micro-electrode array (MEA) recordings, we revealed that cortical neurons derived from hiPSCs carrying heterozygous L1342P variant have sig...

Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear if this broad targeting underlies seizure suppression, or if a specific output may be sufficient. To address this question, we used the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, male and female animals, and a dual-virus approach to selectively label and manipulate fastigial outputs. We examined fastigial neurons projecting to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus, and found that these comprise largely non-overlapping populations of neurons which send collaterals to unique sets of additional, somewhat overlapping, thalamic and brainstem regions. We found that neither optogenetic stimulation of superior colliculus nor reticula...

Accumulating evidence in the past decade implicates histone modifying enzymes, such as class I histone deacetylases (HDACs), in learning and memory, and recently habit formation. However, it is unclear whether HDACs play roles in complex cognitive function. To address this issue, we examined the role of dorsal striatal HDAC5, a class II HDAC, in reward-guided decision-making and associated neural encoding in rats. We first injected adeno-associated virus to overexpress a nuclear-localized HDAC5 in dorsal striatum (DS). We then recorded neural correlates from dorsolateral striatum (DLS) as rats performed two reward-guided choice tasks, in which we manipulated either the size of or delay to reward. During these tasks, rats first learned which of two options led to the better reward, and then reversed those contingencies in a second block of trials. We found that rats with HDAC5 overexpression in DS responded faster and chose higher value reward more often during the first block of trials, but were less able ...

The primary somatosensory cortex (S1) plays a critical role in processing multiple somatosensations, but the mechanism underlying the representation of different submodalities of somatosensation in S1 remains unclear. Using in vivo two-photon calcium imaging that simultaneously monitors hundreds of layer 2/3 pyramidal S1 neurons of awake male mice, we examined neuronal responses triggered by mechanical, thermal or pruritic stimuli. We found that mechanical, thermal and pruritic stimuli activated largely overlapping neuronal populations in the same somatotopic S1 subregion. Population decoding analysis revealed that the local neuronal population in S1 encoded sufficient information to distinguish different somatosensory submodalities. Although multimodal S1 neurons responding to multiple types of stimuli exhibited no spatial clustering, S1 neurons preferring mechanical and thermal stimuli tended to show local clustering. These findings demonstrated the coding scheme of different submodalities of somatosensa...

Brain-machine interfaces (BMIs) for reaching have enjoyed continued performance improvements, yet there remains significant need for BMIs that control other movement classes. Recent scientific findings suggest that the intrinsic covariance structure of neural activity depends strongly on movement class, potentially necessitating different decode algorithms across classes. To address this possibility, we developed a self-motion BMI based on cortical activity as monkeys cycled a hand-held pedal to progress along a virtual track. Unlike during reaching, we found no high-variance dimensions that directly correlated with to-be-decoded variables. This was due to no neurons having consistent correlations between their responses and kinematic variables. Yet we could decode a single variable – self-motion – by non-linearly leveraging structure that spanned multiple high-variance neural dimensions. Resulting online BMI-control success rates approached those during manual control. These findings make two broad points...

In natural conversations, listeners must attend to what others are saying while ignoring extraneous background sounds. Recent studies have used encoding models to predict electroencephalography (EEG) responses to speech in noise-free listening situations, sometimes referred to as “speech tracking.” Researchers have analyzed how speech tracking changes with different types of background noise. It is unclear, however, whether neural responses from acoustically rich, naturalistic environments with and without background noise can be generalized to more controlled stimuli. If encoding models for acoustically rich, naturalistic stimuli are generalizable to other tasks, this could aid in data collection from populations of individuals who may not tolerate listening to more controlled and less engaging stimuli for long periods of time. We recorded noninvasive scalp EEG while 17 human participants (8 male/9 female) listened to speech without noise and audiovisual speech stimuli containing overlapping speakers and ...

Neural response properties that typify primary sensory afferents are critical to fully appreciate because they establish and, ultimately represent, the fundamental coding design used for higher-level processing. Studies illuminating the center-surround receptive fields of retinal ganglion cells, for example, were ground-breaking because they determined the foundation of visual form detection. For the auditory system, a basic organizing principle of the spiral ganglion afferents is their extensive electrophysiological heterogeneity establishing diverse intrinsic firing properties in neurons throughout the spiral ganglion. Moreover, these neurons display an impressively large array of neurotransmitter receptor types that are responsive to efferent feedback. Thus, electrophysiological diversity and its neuromodulation are a fundamental encoding mechanism contributed by the primary afferents in the auditory system. To place these features into context, we evaluated the effects of hyperpolarization and cAMP on ...