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SummaryEmotional events comprise our strongest and most valuable memories, yet it is unknown how the brain prioritizes emotional information for storage. Here, we examined the neural basis of this prioritization using direct brain recording, deep brain stimulation, and psychometric assessment, with human subjects performing an episodic memory task in which they showed improved performance for emotional stimuli. During the task, high-frequency activity (HFA), a correlate of neuronal spiking activity, increased in both the hippocampus and amygdala when subjects successfully encoded emotionally arousing stimuli. Applying inhibitory electrical stimulation to these regions decreased HFA and specifically reversed the enhancement of memory for emotional stimuli, indicating that neuronal activity in the amygdalohippocampal circuit has a direct role in prioritizing emotional memories. Finally, we found abnormal patterns of amygdalohippocampal HFA in depressed individuals which correlated with a bias for negative memories in these subjects. Going forward, targeted modulation that upregulates neuronal excitation in the amygdalohippocampal circuit may have a causal and translational role in modulating emotional memory.

Numerous genetic and postmortem studies link N-methyl-d-aspartate receptor (NMDAR) dysfunction with schizophrenia, forming the basis of the popular glutamate hypothesis. Neuronal NMDAR abnormalities are consistently reported from both basic and clinical experiments, however, non-neuronal cells also contain NMDARs, and are rarely, if ever, considered in the discussion of glutamate action in schizophrenia. We offer an examination of recent discoveries elucidating the actions and consequences of NMDAR activation in the neuroendothelium. While there has been mixed literature regarding blood flow alterations in the schizophrenia brain, in this review, we posit that some common findings may be explained by neuroendothelial NMDAR dysfunction. In particular, we emphasize that endothelial NMDARs are key mediators of neurovascular coupling, where increased neuronal activity leads to increased blood flow. Based on the broad conclusions that hypoperfusion is a neuroanatomical finding in schizophrenia, we discuss potential mechanisms by which endothelial NMDARs contribute to this disorder. We propose that endothelial NMDAR dysfunction can be a primary cause of neurovascular abnormalities in schizophrenia. Importantly, functional MRI studies using BOLD signal as a proxy for neuron activity should be considered in a new light if neurovascular coupling is impaired in schizophrenia. This review is the first to propose that NMDARs in non-excitable cells play a role in schizophrenia.

A neuronal ensemble represents the concomitant activity of a specific group of neurons that could encompass a broad repertoire of brain functions such as motor, perceptual, memory or cognitive states. On the other hand, a memory engram portrays the physical manifestation of memory or the changes that enable learning and retrieval. Engram studies focused for many years on finding where memories are stored as in, which cells or brain regions represent a memory trace, and disregarded the investigation of how neuronal activity patterns give rise to such memories. Recent experiments suggest that the association and reactivation of specific neuronal groups could be the main mechanism underlying the brain's ability to remember past experiences and envision future actions. Thus, the growing consensus is that the interaction between neuronal ensembles could allow sequential activity patterns to become memories and recurrent memories to compose complex behaviors. The goal of this review is to propose how the neuronal ensemble framework could be translated and useful to understand memory processes.

Seizures are thought to arise from an imbalance of excitatory and inhibitory neuronal activity. While most classical studies suggest excessive excitatory neural activity plays a generative role, some recent findings challenge this view and instead argue that excessive activity in inhibitory neurons initiates seizures. We investigated this question of imbalance in a zebrafish seizure model with multi-regional two-photon imaging of excitatory and inhibitory neuronal activity using a nuclear-localized calcium sensor. We found that seizures consistently initiated in circumscribed zones of the midbrain before propagating to other brain regions. Excitatory neurons were both more prevalent and more likely to be recruited than inhibitory neurons in initiation as compared with propagation zones. These findings support a mechanistic picture whereby seizures initiate in a region of hyper-excitation, then propagate more broadly once inhibitory restraint in the surround is overcome.TeaserWe uncover the roles of excitation and inhibition during seizures, thus opening a path to more targeted therapy of epilepsy.

Impaired temporal resolution of the central auditory system has long been suggested to contribute to speech understanding deficits in the elderly. However, it has been difficult to differentiate between direct age-related central deficits and indirect effects of confounding peripheral age-related hearing loss on temporal resolution. To differentiate this, we measured temporal acuity in the inferior colliculus (IC) of aged CBA/J and C57BL/6 mice, as a model of aging with and without concomitant hearing loss. We used two common measures of auditory temporal processing: gap detection as a measure of temporal fine structure and amplitude-modulated noise as a measure of envelope sensitivity. Importantly, auditory temporal acuity remained precise in the IC of old CBA/J mice when no or only minimal age-related hearing was present. In contrast, temporal acuity was only indirectly reduced by the presence of age-related hearing loss in aged C57BL/6 mice, not by affecting the brainstem precision, but by affecting the signal-to-noise ratio of the neuronal activity in the IC. This demonstrates that indirect effects of age-related peripheral hearing loss likely remain an important factor for temporal processing in aging in comparison to 'pure' central auditory decline itself. It also draws attention to the issue that the threshold difference between ‘nearly normal’ or ‘clinically normal hearing aging subjects in comparison to normal hearing young subjects still can have indirect effects on central auditory neural representations of temporal processing.

To assess the efficacy of therapy in patients with asymptomatic brain lesions, such as «silent» brain infarcts (SBI), a number of electroencephalography (EEG) parameters can be used, as there is a correlation between EEG parameters and indices of neuronal metabolism, and consequence of progressive EEG changes is associated closely with both current ischemia and recovery after ischemic events. The analysis of an influence of 3-week treatment course of Cerebrolysin (in the background of basic therapy) on the bioelectric brain activity was performed in 36 patients (mean age 54.00 ± 3.22 years) with magnetic resonance imaging (MRI) signs of single SBI and in 24 patients (mean age 67.89 ± 1.84 years) with MRI signs of multiple SBI. The study shows that to assess the treatment efficacy in patients with asymptomatic brain lesions, EEG-correlates of disorders of the cerebral blood flow (a general EEG spectral power; index, spectral power, density of α- and δ-rhythms; (δ+θ)/(α+β) and α/δ ratio; the brain symmetry index (BSI) can be used. According to the most studies of EEG-parameters, Cerebrolysin had a positive and diffuse impact on the levels of the bioelectric brain activity in patients with SBI. In patients with asymptomatic brain lesions, BSI and EEG-parameters associated with neuronal activity of α-rhythm sources appeared to be most sensitive to the therapy.

Thalamic stroke leads to ataxia if the cerebellum-receiving ventrolateral thalamus (VL) is affected. The compensation mechanisms for this deficit are not well understood, particularly the roles that single neurons and specific neuronal subpopulations outside the thalamus play in recovery. The goal of this study was to clarify neuronal mechanisms of the motor cortex involved in mitigation of ataxia during locomotion when part of the VL is inactivated or lesioned. In freely ambulating cats, we recorded the activity of neurons in layer V of the motor cortex as the cats walked on a flat surface and horizontally placed ladder. We first reversibly inactivated ∼10% of the VL unilaterally using glutamatergic transmission antagonist CNQX and analyzed how the activity of motor cortex reorganized to support successful locomotion. We next lesioned 50%–75% of the VL bilaterally using kainic acid and analyzed how the activity of motor cortex reorganized when locomotion recovered. When a small part of the VL was inactivated, the discharge rates of motor cortex neurons decreased, but otherwise the activity was near normal, and the cats walked fairly well. Individual neurons retained their ability to respond to the demand for accuracy during ladder locomotion; however, most changed their response. When the VL was lesioned, the cat walked normally on the flat surface but was ataxic on the ladder for several days after lesion. When ladder locomotion normalized, neuronal discharge rates on the ladder were normal, and the shoulder-related group was preferentially active during the stride’s swing phase. NEW & NOTEWORTHY This is the first analysis of reorganization of the activity of single neurons and subpopulations of neurons related to the shoulder, elbow, or wrist, as well as fast- and slow-conducting pyramidal tract neurons in the motor cortex of animals walking before and after inactivation or lesion in the thalamus. The results offer unique insights into the mechanisms of spontaneous recovery after thalamic stroke, potentially providing guidance for new strategies to alleviate locomotor deficits after stroke.

Inflammation or trauma occurring on one side of the body can cause pathological pain on the contralateral noninjured side in a phenomenon called mirror-image pain (MIP). Although some potential mechanisms involved in MIP have been reported, including those involving the immune system and glial cells as well as neural mechanisms, the molecular mechanisms are not well understood. In this study, we aimed to understand the molecular mechanisms in MIP using quantitative proteomics and whole-cell patch clamp recordings. Behavioral test results showed that complete Freund's adjuvant could induce MIP in the mice. The results of isobaric tags for relative and absolute quantification (iTRAQ) quantitative proteomics showed that 108 proteins were dysregulated, and these proteins may represent potential targets. Furthermore, bioinformatics analysis was applied to explore the potential molecular mechanisms during MIP after complete Freund's adjuvant (CFA) treatment. Parallel reaction monitoring (PRM) results showed that PKCδ and seven other dysregulated proteins were related to MIP after CFA treatment. Patch clamp recording results showed that CFA treatment could increase intrinsic excitability and spontaneous firing in spinal cord neurons during MIP. In summary, we found that CFA could induce MIP. The results of proteomic research on the spinal cord after CFA treatment could provide new insight into the molecular mechanisms of MIP. Moreover, the neuronal activity of spinal cord neurons was upregulated during MIP after CFA treatment. In summary, the results of the spinal cord proteomic profile provide a potential molecular mechanism for understanding MIP.

To truly understand cerebellar function, it is essential to address the effect of the numerous peptides present within cerebellar circuits and the role they play in modulating neuronal activity in the cerebellum. To date, at least 22 neuropeptides have been identified in the cerebellum. However, relatively little is conclusively known about the modulatory role of the vast majority of these peptides. The potential role of three peptides is reviewed. Future research should focus on defining transduction pathways activated following binding of these peptides to their G-protein-coupled receptors, defining the function of peptides produced by cerebellar neurons such as Purkinje cells or Golgi cells, and describing how neuropeptides modulate cerebellar nuclear neurons, which represent the output of the cerebellum.

Mounting evidence suggests that amyloid-β (Aβ) and vascular etiologies are intertwined in the pathogenesis of Alzheimer’s disease (AD). Blood-oxygen-level-dependent (BOLD) signals, measured by resting-state functional MRI (rs-fMRI), are associated with neuronal activity and cerebrovascular hemodynamics. Nevertheless, it is unclear if BOLD fluctuations are associated with Aβ deposition in individuals at high risk of AD. Thirty-three patients with amnestic mild cognitive impairment underwent rs-fMRI and AV45 PET. The AV45 standardized uptake value ratio (AV45-SUVR) was calculated using cerebral white matter as reference, to assess Aβ deposition. The whole-brain normalized amplitudes of low-frequency fluctuations (sALFF) of local BOLD signals were calculated in the frequency band of 0.01–0.08 Hz. Stepwise increasing physiological/vascular signal regressions on the rs-fMRI data examined whether sALFF-AV45 correlations were driven by vascular hemodynamics, neuronal activities, or both. We found that sALFF and AV45-SUVR were negatively correlated in regions of default-mode and visual networks (precuneus, angular, lingual and fusiform gyri). Regions with higher sALFF had less Aβ accumulation. Correlated cluster sizes in MNI space ( r ≈ −0.47) were reduced from 3018 mm3 to 1072 mm3 with stronger cardiovascular regression. These preliminary findings imply that local brain blood fluctuations due to vascular hemodynamics or neuronal activity can affect Aβ homeostasis.

Non-human primate (NHP) models are essential for developing and translating new treatments that target neural circuit dysfunction underlying human psychopathology. As a proof-of-concept for treating neuropsychiatric disorders, we used a NHP model of pathological anxiety to investigate the feasibility of decreasing anxiety by chemogenetically (DREADDs [designer receptors exclusively activated by designer drugs]) reducing amygdala neuronal activity. Intraoperative MRI surgery was used to infect dorsal amygdala neurons with AAV5-hSyn-HA-hM4Di in young rhesus monkeys. Invivo microPET studies with [11C]-deschloroclozapine and postmortem autoradiography with [3H]-clozapine demonstrated selective hM4Di binding in the amygdala, and neuronal expression of hM4Di was confirmed with immunohistochemistry. Additionally, because of its high affinity for DREADDs, and its approved use in humans, we developed an individualized, low-dose clozapine administration strategy to induce DREADD-mediated amygdala inhibition. Compared to controls, clozapine selectively decreased anxiety-related freezing behavior in the human intruder paradigm in hM4Di-expressing monkeys, while coo vocalizations and locomotion were unaffected. These results are an important step in establishing chemogenetic strategies for patients with refractory neuropsychiatric disorders in which amygdala alterations are central to disease pathophysiology.

Patch-clamp electrophysiological recordings of neuronal activity require a large amount of space and equipment. The technique is difficult to master and not conducive to demonstration to more than a few medical students. Therefore, neurophysiological education is mostly limited to classroom-based pedagogies such as lectures. However, the demonstration of concepts such as changes in membrane potential and ion channel activity is best achieved with hands-on approaches. This article details an in silico activity suitable for large groups of medical students that demonstrates the key concepts in neurophysiology using the LabAXON simulation software. Learning activities in our practical include 1) measurements of voltage and time parameters of the neuronal action potential and its relationship to the Nernst potentials of Na+ and K+; 2) determination of the stimulus threshold to evoke action potentials; 3) demonstration of the refractory period of an action potential; and 4) voltage-clamp experiments to determine the current-voltage relationship of voltage-gated Na+ and K+ channels and the voltage dependence of, and recovery from, inactivation of voltage-gated Na+ channels. We emphasized the accuracy of quantitative measurements as well as the correct use of units. The level of difficulty of the activity can be altered through different multiple choice questions relating to material introduced in the associated lectures. This practical activity is suitable for different class sizes and is adaptable for delivery with online platforms. Student feedback showed that the students felt the activity helped them consolidate their understanding of the lecture material.

Neuroimmune signaling is increasingly identified as a critical component of various illnesses, including chronic pain, substance use disorder, and depression. However, the underlying neural mechanisms remain unclear. Proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), may play a role by modulating synaptic function and long-term plasticity. The midbrain structure periaqueductal gray (PAG) plays a well-established role in pain processing, and although TNF-α inhibitors have emerged as a therapeutic strategy for pain-related disorders, the impact of TNF-α on PAG neuronal activity has not been thoroughly characterized. Recent studies have identified subpopulations of ventrolateral PAG (vlPAG) with opposing effects on nociception, with dopamine (DA) neurons driving pain relief in contrast to GABA neurons. Therefore, we used slice physiology to examine the impact of TNF-α on neuronal activity of both these subpopulations. We focused on female mice since the PAG is a sexually dimorphic region and most studies use male subjects, limiting our understanding of mechanistic variations in females. We selectively targeted GABA and DA neurons using transgenic reporter lines. Following exposure to TNF-α, there was an increase in excitability of GABA neurons along with a reduction in glutamatergic synaptic transmission. In DA neurons, TNF-α exposure resulted in a robust decrease in excitability along with a modest reduction in glutamatergic synaptic transmission. Interestingly, TNF-α had no effect on inhibitory transmission onto DA neurons. Collectively, these data suggest that TNF-α differentially affects the function of GABA and DA neurons in female mice and enhances our understanding of how TNF-α-mediated signaling modulates vlPAG function. NEW & NOTEWORTHY This study describes the effects of TNF-α on two distinct subpopulations of neurons in the vlPAG. We show that TNF-α alters both neuronal excitability and glutamatergic synaptic transmission on GABA and dopamine neurons within the vlPAG of female mice. This provides critical new information on the role of TNF-α in the potential modulation of pain, since activation of vlPAG GABA neurons drives nociception, whereas activation of dopamine neurons drives analgesia.

Our study intends to explore the effect of bone marrow mesenchymal stem cells (BMSCs) on neuronal activity and GDNF expression in rats with SCI. Rats were assigned into spinal cord injury group (group S); routinely control group (group R) without spinal incision; and BMSCs group (group B) which received BMSCs treatment with n = 4 rats in each group. The neuronal cell proliferation was detected by cck-8 method, BBB score was used to detect lower limb motor function, GDNF mRNA expression was detected by qRT-PCR, GDNF protein positive expression was measured by immunohistochemistry and cell invasion was assessed by Transwell. Group B rats showed significantly higher BBB score higher than group S (P P P P P P P P P P

Background Activation of the mesolimbic dopamine system is positively reinforcing. After repeated activation, some individuals develop compulsive reward-seeking behavior, which is a core symptom of addiction. However, the underlying neural mechanism remains elusive. Methods We trained mice in a seek-take chain, rewarded by optogenetic dopamine neuron self-stimulation. After compulsivity was evaluated, AMPA/NMDA ratio was measured at three distinct corticostriatal pathways confirmed by retrograde labeling and anterograde synaptic connectivity. Fiber photometry method and chemogenetics were used to parse the contribution of orbitofrontal cortex afferents onto the dorsal striatum (DS) during the behavioral task. We established a causal link between DS activity and compulsivity using optogenetic inhibition. Results Mice that persevered when seeking was punished exhibited an increased AMPA/NMDA ratio selectively at orbitofrontal cortex to DS synapses. In addition, an activity peak of spiny projection neurons in the DS at the moment of signaled reward availability was detected. Chemogenetic inhibition of orbitofrontal cortex neurons curbed the activity peak and reduced punished reward seeking, as did optogenetic hyperpolarization of spiny projection neurons time-locked to the cue predicting reward availability. Conclusions Our results suggest that compulsive individuals display stronger neuronal activity in the DS during the cue predicting reward availability even when at the risk of punishment, nurturing further compulsive reward seeking.

Neuronal activity in the prefrontal cortex (PFC) controls dominance hierarchies in groups of animals. Dopamine (DA) strongly modulates PFC activity mainly through D1 receptors (D1Rs) and D2 receptors (D2Rs). Still, it is unclear how these two subpopulations of DA receptor-expressing neurons in the PFC regulate social dominance hierarchy. Here, we demonstrate distinct roles for prefrontal D1R- and D2R-expressing neurons in establishing social hierarchy, with D1R+neurons determining dominance and D2R+neurons for subordinate.Ex vivowhole-cell recordings revealed that the dominant status of male mice correlates with rectifying AMPAR transmission and stronger excitatory synaptic strength onto D1R+neurons in PFC pyramidal neurons. In contrast, the submissive status is associated with higher neuronal excitability in D2R+neurons. Moreover, simultaneous manipulations of synaptic efficacy of D1R+neurons in dominant male mice and neuronal excitability of D2R+neurons of their male subordinates switch their dominant–subordinate relationship. These results reveal that prefrontal D1R+and D2R+neurons have distinct but synergistic functions in the dominance hierarchy, and DA-mediated regulation of synaptic strengths acts as a powerful behavioral determinant of intermale social rank.SIGNIFICANCE STATEMENTDominance hierarchy exists widely among animals who confront social conflict. Studies have indicated that social status largely relies on the neuronal activity in the PFC, but how dopamine influences social hierarchy via subpopulation of prefrontal neurons is still elusive. Here, we explore the cell type-specific role of dopamine receptor-expressing prefrontal neurons in the dominance–subordinate relationship. We found that the synaptic strength of D1 receptor-expressing neurons determines the dominant status, whereas hyperactive D2-expressing neurons are associated with the subordinate status. These findings highlight how social conflicts recruit distinct cortical microcircuits to drive different behaviors and reveal how D1- and D2-receptor enriched neurocircuits in the PFC establish a social hierarchy.

Monocarboxylate transporters (MCTs) shuttle molecules, including L-lactate, involved in metabolism and cell signaling of the central nervous system. Astrocyte-specific MCT4 is a key component of the astrocyte-neuron lactate shuttle (ANLS) and is important for neuroplasticity and learning of the hippocampus. However, the importance of astrocyte-specific MCT4 in neuroplasticity of the M1 primary motor cortex remains unknown. In this study, we investigated astrocyte-specific MCT4 in motor learning and neuroplasticity of the M1 primary motor cortex using a cell-type specific shRNA knockdown of MCT4. Knockdown of astrocyte-specific MCT4 resulted in impaired motor performance and learning on the accelerating rotarod. In addition, MCT4 knockdown was associated with a reduction of neuronal dendritic spine density and spine width and decreased protein expression of PSD95, Arc, and cFos. Using near-infrared-conjugated 2-deoxyglucose uptake as a surrogate marker for neuronal activity, MCT4 knockdown was also associated with decreased neuronal activity in the M1 primary motor cortex and associated motor regions including the dorsal striatum and ventral thalamus. Our study supports a potential role for astrocyte-specific MCT4 and the ANLS in the neuroplasticity of the M1 primary motor cortex. Targeting MCT4 may serve to enhance neuroplasticity and motor repair in several neurological disorders, including Parkinson's disease and stroke.

Coincident excitation via different sensory modalities encoding objects of positive salience is known to facilitate learning and memory. With a view to dissect the contribution of visual cues in inducing adaptive neural changes, we monitored the lever press activity of a rat conditioned to self-administer sweet food pellets in the presence/absence of light cues. Application of light cues facilitated learning and consolidation of long-term memory. The superior colliculus (SC) of rats trained on light cue showed increased neuronal activity, dendritic branching, and brain-derived neurotrophic factor (BDNF) protein and mRNA expression. Concomitantly, the hippocampus showed augmented neurogenesis as well as BDNF protein and mRNA expression. While intra-SC administration of U0126 (inhibitor of ERK 1/2 and long-term memory) impaired memory formation, lidocaine (local anaesthetic) hindered memory recall. The light cue–dependent sweet food pellet self-administration was coupled with increased efflux of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens shell (AcbSh). In conditioned rats, pharmacological inhibition of glutamatergic signalling in dentate gyrus (DG) reduced lever press activity, as well as DA and DOPAC secretion in the AcbSh. We suggest that the neuroplastic changes in the SC and hippocampus might represent memory engrams sculpted by visual cues encoding reward information.

Cholinergic interneurons (CINs) in the striatum respond to salient stimuli with a multiphasic response, including a pause, in neuronal activity. Slice-physiology experiments have shown the importance of dopamine D2 receptors (D2Rs) in regulating CIN pausing, yet the behavioral significance of the CIN pause and its regulation by dopamine in vivo is still unclear. Here, we show that D2R upregulation in CINs of the nucleus accumbens (NAc) lengthens the pause in CIN activity ex vivo and enlarges a stimulus-evoked decrease in acetylcholine (ACh) levels during behavior. This enhanced dip in ACh levels is associated with a selective deficit in the learning to inhibit responding in a Go/No-Go task. Our data demonstrate, therefore, the importance of CIN D2Rs in modulating the CIN response induced by salient stimuli and point to a role of this response in inhibitory learning. This work has important implications for brain disorders with altered striatal dopamine and ACh function, including schizophrenia and attention-deficit hyperactivity disorder (ADHD).

The brain requires an adequate supply of oxygen and nutrients to maintain proper function as neuronal activity varies. This is achieved, in part, through neurovascular coupling mechanisms that mediate local increases in blood flow through the dilation of arterioles and capillaries. The role of astrocytes in mediating this functional hyperemia response is controversial. Specifically, the function of astrocyte Ca(2+) signaling is unclear. Cortical arterioles dilate in the absence of astrocyte Ca(2+) signaling, but previous work suggests that Ca(2+) increases are necessary for capillary dilation. This question has not been fully addressed in vivo, however, and we have reexamined the role of astrocyte Ca(2+) signaling in vessel dilation in the barrel cortex of awake, behaving mice. We recorded evoked vessel dilations and astrocyte Ca(2+) signaling in response to whisker stimulation. Experiments were carried out on WT and IP3R2 KO mice, a transgenic model where astrocyte Ca(2+) signaling is substantially reduced. Compared to WT mice at rest, Ca(2+) signaling in astrocyte endfeet contacting capillaries increased by 240% when whisker stimulation evoked running. In contrast, Ca(2+) signaling was reduced to 9% of WT values in IP3R2 KO mice. In all three conditions, however, the amplitude of capillary dilation was largely unchanged. In addition, the latency to the onset of astrocyte Ca(2+) signaling lagged behind dilation onset in most trials, although a subset of rapid onset Ca(2+) events with latencies as short as 0.15 s occurred. In summary, we found that whisker stimulation-evoked capillary dilations occurred independent of astrocyte Ca(2+) increases in the cerebral cortex.

SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking out SORCS2 in a human neuronal cell line increased Topoisomerase IIβ-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA breaks in vitro, suggesting that the observed differences may not be the result of aberrant neuronal activity in these cells. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.

The time course of the neuronal activity in the brain network, the neurodynamics, reflects the structure and functionality of the generating neuronal pools. Here, using the intracranial stereo-electroencephalographic (sEEG) recordings of the public Montreal Neurological Institute (MNI) atlas, we investigated the neurodynamics of primary motor (M1), somatosensory (S1) and auditory (A1) cortices measuring power spectral densities (PSD) and Higuchi fractal dimension (HFD) in the same subject (M1 vs. S1 in 16 subjects, M1 vs. A1 in 9, S1 vs. A1 in 6). We observed specific spectral features in M1, which prevailed above beta band, S1 in the alpha band, and A1 in the delta band. M1 HFD was higher than S1, both higher than A1. A clear distinction of neurodynamics properties of specific primary cortices supports the efforts in cortical parceling based on this expression of the local cytoarchitecture and connectivity. In this perspective, we selected within the MNI intracortical database a first set of primary motor, somatosensory and auditory cortices’ representatives to query in recognizing ongoing patterns of neuronal communication. Potential clinical impact stands primarily in exploiting such exchange patterns to enhance the efficacy of neuromodulation intervention to cure symptoms secondary to neuronal activity unbalances.

Joshua Crawford, Sufang Liu, Feng Tao Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX, 75246, USACorrespondence: Feng TaoDepartment of Biomedical Sciences, Texas A&M University College of Dentistry, 3302 Gaston Ave., Dallas, TX, 75246, USATel +1-214-828-8272Fax +1-214-874-4538Email ftao81@tamu.eduBackground: Highlighted by the current opioid epidemic, identifying novel therapies to treat chronic trigeminal neuropathic pain is a critical need. To develop these treatments, it is necessary to have viable targets in the brain to act on. Historically, neural tracing studies have been extremely useful in determining connections between brain areas but do not provide information about the functionality of these connections. Combining optogenetics and behavioral observation allows researchers to determine whether a particular brain area is involved in the regulation of such behavior. The addition of multi-channel electrophysiological recording provides information on real-time neuronal activity in the specific neuronal pathway.Methods: Male C57/BL/6J mice (8-week-old) underwent either chronic constriction injury of infraorbital nerve (CCI-ION) or a sham surgery and were injected with either channelrhodopsin (ChR2) or a control virus in the hypothalamic A11 nucleus. Two weeks after CCI-ION, they were tested in real-time place preference (RTPP), while neuronal activity in the spinal trigeminal nucleus caudalis (Sp5C) was recorded.Results: Optogenetic excitation of the A11 neurons results in more time spent in the stimulation chamber during RTPP testing. Additionally, stimulation of the A11 results in a greater number of neuronal activity increase in the Sp5C in animals with the injection of AAV carrying ChR2 compared to animals injected with a control virus or that underwent a sham surgery.Conclusion: In vivo multi-channel electrophysiological recording, optogenetic stimulation, and behavioral observation can be combined in a mouse model of chronic trigeminal neuropathic pain to validate brain areas involved in the modulation of such pain.Keywords: optogenetic stimulation, multi-channel recording, real-time place preference

Background Previous studies have shown that neurons of the cerebral cortex can be injured by implantation of, and stimulation with, implanted microelectrodes. Objectives Objective 1 was to determine parameters of microstimulation delivered through multisite intracortical microelectrode arrays that will activate neurons of the feline cerebral cortex without causing loss of neurons. Objective 2 was to determine if the stimulus parameters that induced loss of cortical neurons differed for all cortical neurons vs. the subset of inhibitory neurons expressing parvalbumin. Methods The intracortical microstimulation was applied for 7 h/day for 20 days (140 h). Microelectrode site areas were 2000 and 4000 μm2, Q was 2-8 nanocoulombs (nC) at 50 Hz, and QD was 50-400 μcoulombs/cm2. Results Neuron loss due to stimulation was minimal at Q = 2 Ncp, but at 8 Ncp, 20%-50% of neurons within 250 μm of the stimulated microelectrodes were lost, compared to unstimulated microelectrodes. Loss was greatest in tissue facing electrode sites. Stimulation-induced loss was similar for neurons labeled for NeuN and for inhibitory neurons expressing parvalbumin. Correlation between neuron loss and QD was not significant. Electrodes in the medullary pyramidal tract recorded neuronal activity evoked by stimulation in the cerebral cortex. The pyramidal neurons were activated by intracortical stimulation of 2 nC/phase. 140 h of microstimulation at 2 nC/phase and 50 Hz induced minimal neuron loss.

AgRP neurons trigger one of the most potent orexigenic responses and are both necessary and sufficient for feeding. Recent technical advances for monitoring in vivo neuronal activity have revisited a previously well-established model of AgRP neurons' feeding regulatory effects. Our current understanding of AgRP neurons has increased in complexity and revealed a fine-tuned regulation of their activity dynamics across the whole sequence of feeding-related behaviours. This review focuses on recent studies that refined and re-evaluated our understanding of the regulatory principles and behavioural effects of AgRP circuits. We aim to cover major discoveries on the dynamic regulation of AgRP neuronal activity by exteroceptive and interoceptive food-related cues, their pleiotropic effects in feeding and whole-body homeostasis, and the associated AgRP circuits. The function and regulation of AgRP neuron will be sequentially discussed across the temporal series of behavioural and physiological changes occurring during the appetitive (food craving and foraging), the anticipatory (discovery of food-predicting cues), and the consummatory/post-ingestive phase of feeding (calorie ingestion).

Sensory neurons have recently emerged as components of the tumor microenvironment. Nevertheless, whether sensory neuronal activity is important for tumor progression remains unknown. Here we used Designer Receptors Exclusively Activated by a Designer Drug (DREADD) technology to inhibit or activate sensory neurons’ firing within the melanoma tumor. Melanoma growth and angiogenesis were accelerated following inhibition of sensory neurons’ activity and were reduced following overstimulation of these neurons. Sensory neuron-specific overactivation also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of melanoma biopsies revealed that increased expression of sensory neurons-related genes within melanoma was associated with improved survival. These findings suggest that sensory innervations regulate melanoma progression, indicating that manipulation of sensory neurons’ activity may provide a valuable tool to improve melanoma patients’ outcomes. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01273-9.

ASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy. These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters. Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors. These results have revealed the critical role of ASH1L in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for ASH1L-associated brain diseases., ASH1L haploinsufficiency is strongly linked to autism, despite the unknown mechanism. Here, the authors show that ASH1L deficiency in prefrontal cortex causes the downregulation of synaptic genes, leading to seizures, which is rescued by chemogenetic and pharmacological restoration of excitation/inhibition balance.

A common feature across neuropsychiatric disorders is inability to discontinue an action or thought once it has become detrimental. Reversal learning, a hallmark of executive control, requires plasticity within cortical, striatal and limbic circuits and is highly sensitive to disruption of N-methyl-(D)-aspartate receptor (NMDAR) function. In particular, selective deletion or antagonism of GluN2B containing NMDARs in cortical regions including the orbitofrontal cortex (OFC), promotes maladaptive perseveration. It remains unknown whether GluN2B functions to maintain local cortical activity necessary for reversal learning, or if it exerts a broader influence on the integration of neural activity across cortical and subcortical systems. To address this question, we utilized in vivo electrophysiology to record neuronal activity and local field potentials (LFP) in the orbitofrontal cortex and dorsal striatum (dS) of mice with deletion of GluN2B in neocortical and hippocampal principal cells while they performed touchscreen reversal learning. Reversal impairment produced by corticohippocampal GluN2B deletion was paralleled by an aberrant increase in functional connectivity between the OFC and dS. These alterations in coordination were associated with alterations in local OFC and dS firing activity. These data demonstrate highly dynamic patterns of cortical and striatal activity concomitant with reversal learning, and reveal GluN2B as a molecular mechanism underpinning the timing of these processes.

Melatonin has been well documented for its neuroprotective role through inhibiting oxidative stress against traumatic brain injury (TBI). However, the specific role of melatonin and the exact effects on cell responses (neurons, astrocytes, and microglia) in different brain regions are unclear. Here, we subjected mice to closed head injury, to establish a repeated mild TBI model and detect neuronal activity and glial responses in cognition-related brain regions after melatonin administration. Melatonin only showed cognitive enhancement if administered during early pathological stages, but not in late (chronic) stages. Additionally, we observed a significant increase in neuronal activity and inhibition of astrocyte reactivation in medial prefrontal cortex and hippocampus, but not in other cognitive deficit related brain regions. Furthermore, by activating astrocytes in these brain regions, we found neuronal activity upregulation and cognitive improvement following melatonin treatment. Therefore, we concluded that melatonin administration during the early stages of TBI is necessary to inhibit astrocyte reactivation and to promote cognitive function. Our results provide evidence for use of melatonin for cognitive improvement after TBIs.

Imaging the activity of neurons that are widely distributed across brain regions deep in scattering tissue at high speed remains challenging. Here, we introduce an open-source system with Dual Independent Enhanced Scan Engines for Large field-of-view Two-Photon imaging (Diesel2p). Combining optical design, adaptive optics, and temporal multiplexing, the system offers subcellular resolution over a large field-of-view of ~25 mm2, encompassing distances up to 7 mm, with independent scan engines. We demonstrate the flexibility and various use cases of this system for calcium imaging of neurons in the living brain., Imaging of neuronal activity across distant brain regions is challenging. Here, the authors introduce a two-photon microscope with two independently controlled scan engines, and demonstrate calcium imaging with subcellular resolution in brain regions up to 7 mm apart simultaneously.

There is an emerging body of literature suggesting that unlike the chronic neuroinflammatory response, acute neuroinflammation is self-regulated and is beneficial for central nervous system homeostasis and cognitive integrity. However, the neurophysiological alterations upon acute neuroinflammation and their implications on cognitive function remain poorly understood. In the present study, we reliably established a mouse model of acute and self-limiting neuroinflammation by administering a single intraperitoneal injection of low-dose lipopolysaccharide, which induced reversible sickness behavior and increased pro-inflammatory cytokine expression in the medial prefrontal cortex (mPFC). During acute neuroinflammation, fast-spiking parvalbumin-expressing interneurons (PV interneurons) in the mPFC exhibited a hyperexcitable phenotype exemplified by increased input resistance, decreased rheobase current, and a higher frequency of action potentials. Furthermore, PV interneurons in the prelimbic subregion of the mPFC were excessively recruited into circuits supporting novel object recognition memory, which remained intact after acute neuroinflammation. Together, our findings suggest that alterations in PV neuronal excitability resulting from acute neuroinflammation may mediate neuronal recruitment and confer a beneficial outcome on functional integrity of NOR circuit in the mPFC.

Background: Abnormal morphology and function of neurons in the prefrontal cortex (PFC) are associated with cognitive deficits in rodent models of Alzheimer’s disease (AD), particularly in cortical layer-5 pyramidal neurons that integrate inputs from different sources and project outputs to cortical or subcortical structures. Pyramidal neurons in layer-5 of the PFC can be classified as two subtypes depending on the inducibility of prominent hyperpolarization-activated cation currents (h-current). However, the differences in the neurophysiological alterations between these two subtypes in rodent models of AD remain poorly understood. Objective: To investigate the neurophysiological alterations between two subtypes of pyramidal neurons in hAPP-J20 mice, a transgenic model for early onset AD. Methods: The synaptic transmission and intrinsic excitability of pyramidal neurons were investigated using whole-cell patch recordings. The morphological complexity of pyramidal neurons was detected by biocytin labelling and subsequent Sholl analysis. Results: We found reduced synaptic transmission and intrinsic excitability of the prominent h-current (PH) cells but not the non-PH cells in hAPP-J20 mice. Furthermore, the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which mediated h-current was disrupted in the PH cells of hAPP-J20 mice. Sholl analysis revealed that PH cells had less dendritic intersections in hAPP-J20 mice comparing to control mice, implying that a lower morphological complexity might contribute to the reduced neuronal activity. Conclusion: These results suggest that the PH cells in the medial PFC may be more vulnerable to degeneration in hAPP-J20 mice and play a sustainable role in frontal dysfunction in AD.

Friedreich ataxia (FRDA) is a progressive autosomal recessive disease. While motor dysfunction is the primary neurological hallmark, little is known about the underlying neurobiological changes associated with motor deficits over the course of disease. We investigated the hypothesis that progressive functional changes in both the cerebellum and cerebrum are related to longitudinal changes in performance on complex motor tasks in individuals with FRDA. Twenty-two individuals with FRDA and 28 controls participated over 24 months. The longitudinal investigation included finger tapping tasks with different levels of complexity (i.e., visually cued, multi-finger; self-paced, single finger), performed in conjunction with fMRI acquisitions, to interrogate changes in the neurobiology of motor and attentional brain networks including the cerebellum and cerebrum. We demonstrated evidence for significant longitudinal decreased cerebral fMRI activity over time in individuals with FRDA, relative to controls, during an attentionally-demanding motor task (visually cued tapping of multiple fingers) in six cerebral regions: right and left superior frontal gyri, right superior temporal gyrus, right primary somatosensory area, right anterior cingulate cortex, and right medial frontal gyrus. Importantly, longitudinal decreased activity was associated with more severe disease status at baseline, higher GAA1 repeat length and earlier age of onset. These findings suggest a dynamic pattern of neuronal activity in motor, attention and executive control networks over time in individuals with FRDA, which is associated with increased disease severity at baseline, increased GAA1 repeat length and earlier age at onset.

Homeostatic plasticity maintains network stability by adjusting excitation, inhibition, or the intrinsic excitability of neurons, but the developmental regulation and coordination of these distinct forms of homeostatic plasticity remains poorly understood. A major contributor to this information gap is the lack of a uniform paradigm for chronically manipulating activity at different developmental stages. To overcome this limitation, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to directly suppress neuronal activity in layer (L) 2/3 of mouse primary visual cortex (V1) at two important developmental timepoints: the classic visual system critical period (CP, P24-29), and adulthood (P45-55). We show that 24 hours of DREADD-mediated activity suppression simultaneously induces excitatory synaptic scaling up and intrinsic homeostatic plasticity in L2/3 pyramidal neurons during the CP, consistent with previous observations using prolonged visual deprivation. Importantly, manipulations known to block these forms of homeostatic plasticity when induced pharmacologically or via visual deprivation also prevented DREADD-induced homeostatic plasticity. We next used the same paradigm to suppress activity in adult animals. Surprisingly, while excitatory synaptic scaling persisted into adulthood, intrinsic homeostatic plasticity was completely absent. Finally, we found that homeostatic changes in quantal inhibitory input onto L2/3 pyramidal neurons were absent during the CP but present in adults. Thus, the same population of neurons can express distinct sets of homeostatic plasticity mechanisms at different development stages. Our findings suggest that homeostatic forms of plasticity can be recruited in a modular manner according to the evolving needs of a developing neural circuit.Significance statementDeveloping brain circuits are subject to dramatic changes in inputs that could destabilize activity if left uncompensated. This compensation is achieved through a set of homeostatic plasticity mechanisms that provide slow, negative feedback adjustments to excitability. Given that circuits are subject to very different destabilizing forces during distinct developmental stages, the forms of homeostatic plasticity present in the network must be tuned to these evolving needs. Here we developed a method to induce comparable homeostatic compensation during distinct developmental windows, and found that neurons in the juvenile and mature brain engage strikingly different forms of homeostatic plasticity. Thus, homeostatic mechanisms can be recruited in a modular manner according to the developmental needs of the circuit.

Background: Transcranial photobiomodulation (tPBM) has recently emerged as a potential cognitive enhancement technique and clinical treatment for various neuropsychiatric and neurodegenerative disorders by delivering invisible near-infrared light to the scalp and increasing energy metabolism in the brain. Objective: We assessed whether transcranial photobiomodulation with near-infrared light modulates cerebral electrical activity through electroencephalogram (EEG) and cerebral blood flow (CBF). Methods: We conducted a single-blind, sham-controlled pilot study to test the effect of continuous (c-tPBM), pulse (p-tPBM), and sham (s-tPBM) transcranial photobiomodulation on EEG oscillations and CBF using diffuse correlation spectroscopy (DCS) in a sample of ten healthy subjects [6F/4 M; mean age 28.6±12.9 years]. c-tPBM near-infrared radiation (NIR) (830 nm; 54.8 mW/cm2; 65.8 J/cm2; 2.3 kJ) and p-tPBM (830 nm; 10 Hz; 54.8 mW/cm2; 33%; 21.7 J/cm2; 0.8 kJ) were delivered concurrently to the frontal areas by four LED clusters. EEG and DCS recordings were performed weekly before, during, and after each tPBM session. Results: c-tPBM significantly boosted gamma (t = 3.02, df = 7, p

Neurovascular coupling is a key control mechanism in cerebral blood flow (CBF) regulation. Importantly, this process was demonstrated to be affected in several neurological disorders, including epilepsy. Neurovascular coupling (NVC) is the basis for functional brain imaging, such as PET, SPECT, fMRI, and fNIRS, to assess and map neuronal activity, thus understanding NVC is critical to properly interpret functional imaging signals. However, hemodynamics, as assessed by these functional imaging techniques, continue to be used as a surrogate to map seizure activity; studies of NVC and cerebral blood flow control during and following seizures are rare. Recent studies have provided conflicting results, with some studies showing focal increases in CBF at the onset of a seizure while others show decreases. In this brief review article, we provide an overview of the current knowledge state of neurovascular coupling and discuss seizure-related alterations in neurovascular coupling and CBF control.

During cortical development and throughout adulthood, oligodendrocytes add myelin internodes to glutamatergic projection neurons and GABAergic inhibitory neurons. In addition to directing node of Ranvier formation, to enable saltatory conduction and influence action potential transit time, oligodendrocytes support axon health by communicating with axons via the periaxonal space and providing metabolic support that is particularly critical for healthy ageing. In this review we outline the timing of oligodendrogenesis in the developing mouse and human cortex and describe the important role that oligodendrocytes play in sustaining and modulating neuronal function. We also provide insight into the known and speculative impact that myelination has on cortical axons and their associated circuits during the developmental critical periods and throughout life, particularly highlighting their life-long role in learning and remembering.

The involvement of Dexmedetomidine (Dex) has been indicated in postoperative cognitive dysfunction (POCD), while the mechanism is not well characterized. This study estimated the mechanism of Dex in POCD. Rats were anesthetized with sevoflurane (SEV) to evoke POCD and then subjected to Morris water maze test to detect the cognitive and behavioral function. Then, the damage of hippocampus and cortex, and apoptosis and activity of neurons were examined. Microarray analysis was performed to screen out the differentially expressed microRNAs (miRs) in rats after Dex treatment. The cognitive and behavioral functions and neuronal activity of rats were detected after miR-129 antagomir injection. The target of miR-129 was predicted. The levels of TLR4 and NF-κB p65 in hippocampus and cortex were measured. Dex treatment alleviated SEV-induced behavior and cognitive impairments in rats, promoted neuronal activity and hindered neuronal apoptosis. After treatment with Dex, miR-129 expression was elevated in brain tissues, and the neuroprotection of Dex on POCD rats was partially annulled after injection of miR-129 antagomir. Furthermore, miR-129 targeted TLR4 and prevented the phosphorylation of NF-κB p65. In summary, Dex ameliorated SEV-induced POCD by elevating miR-129 and inhibiting TLR4 and NF-κB p65 phosphorylation. This study may shed new lights on POCD treatment.

The emergence of coordinated network function during nervous system development is often associated with critical periods. These phases are sensitive to activity perturbations during, but not outside, of the critical period, that can lead to permanently altered network function for reasons that are not well understood. In particular, the mechanisms that transduce neuronal activity to regulating changes in neuronal physiology or structure are not known. Here, we take advantage of a recently identified invertebrate model for studying critical periods, the Drosophila larval locomotor system. Manipulation of neuronal activity during this critical period is sufficient to increase synaptic excitation and to permanently leave the locomotor network prone to induced seizures. Using genetics and pharmacological manipulations, we identify nitric oxide (NO)-signaling as a key mediator of activity. Transiently increasing or decreasing NO-signaling during the critical period mimics the effects of activity manipulations, causing the same lasting changes in synaptic transmission and susceptibility to seizure induction. Moreover, the effects of increased activity on the developing network are suppressed by concomitant reduction in NO-signaling and enhanced by additional NO-signaling. These data identify NO signaling as a downstream effector, providing new mechanistic insight into how activity during a critical period tunes a developing network.

Background: fNIRS is a useful tool designed to record the changes in the density of blood’s oxygenated hemoglobin (oxyHb) and deoxygenated hemoglobin (deoxyHb) molecules during brain activity. This method has made it possible to evaluate the hemodynamic changes of the brain during neuronal activity in a completely non-aggressive manner. Objective: The present study has been designed in order to investigate and evaluate the brain cortex activities during imagining of the execution of wrist motor tasks by comparing fMRI and fNIRS imaging methods.Material and Methods: This novel observational Optical Imaging study aims to investigate the brain motor cortex activity during imagining of the right wrist motor tasks in vertical and horizontal directions. In order to perform the study, ten healthy young right-handed volunteers were asked to think about right-hand movements in different directions according to the designed movement patterns. The required data were collected in two wavelengths, including 845 and 763 nanometer using a 48 channeled fNIRS machine. Results: Analysis of the obtained data showed the brain activity patterns during imagining of the execution of a movement are formed in various points of the motor cortex in terms of location. Moreover, depending on the direction of the movement, activity plans have distinguishable patterns.The results showed contralateral M1 were mainly activated during imagining of the motor cortex (p

Gulf War Illness (GWI), a disorder suffered by approximately 200,000 veterans of the first Gulf War, was caused by exposure to low-level organophosphate pesticides and nerve agents in combination with battlefield stress. To elucidate the mechanistic basis of the brain-related symptoms of GWI, human-induced pluripotent stem cells (hiPSCs) derived from veterans with or without GWI were differentiated into forebrain glutamatergic neurons and then exposed to a Gulf War (GW) relevant toxicant regimen consisting of a sarin analog and cortisol, a human stress hormone. Elevated levels of total and phosphorylated tau, reduced microtubule acetylation, altered mitochondrial dynamics/transport, and decreased neuronal activity were observed in neurons exposed to the toxicant regimen. Some of the data are consistent with the possibility that some veterans may have been predisposed to acquire GWI. Wistar rats exposed to a similar toxicant regimen showed a mild learning and memory deficit, as well as cell loss and tau pathology selectively in the CA3 region of the hippocampus. These cellular responses offer a mechanistic explanation for the memory loss suffered by veterans with GWI and provide a cell-based model for screening drugs and developing personalized therapies for these veterans.

Spontaneous neuronal activity strongly impacts stimulus encoding and behavioral responses. We sought to determine the effects of neocortical prestimulus activity on stimulus detection. We trained mice in a selective whisker detection task, in which they learned to respond (lick) to target stimuli in one whisker field and ignore distractor stimuli in the contralateral whisker field. During expert task performance, we used widefield Ca2+ imaging to assess prestimulus and post-stimulus neuronal activity broadly across frontal and parietal cortices. We found that lower prestimulus activity correlated with enhanced stimulus detection: lower prestimulus activity predicted response versus no response outcomes and faster reaction times. The activity predictive of trial outcome was distributed through dorsal neocortex, rather than being restricted to whisker or licking regions. Using principal component analysis, we demonstrate that response trials are associated with a distinct and less variable prestimulus neuronal subspace. For single units, prestimulus choice probability was weak yet distributed broadly, with lower than chance choice probability correlating with stronger sensory and motor encoding. These findings support low amplitude and low variability as an optimal prestimulus cortical state for stimulus detection that presents globally and predicts response outcomes for both target and distractor stimuli.

Sex steroid hormones act on hypothalamic kisspeptin neurons to regulate reproductive neural circuits in the brain. Kisspeptin neurons start to express estrogen receptorsin utero, suggesting steroid hormone action on these cells early during development. Whether neurosteroids are locally produced in the embryonic brain and impinge onto kisspeptin/reproductive neural circuitry is not known. To address this question, we analyzed aromatase expression, a key enzyme in estrogen synthesis, in male and female mouse embryos. We identified an aromatase neuronal network comprising ∼6000 neurons in the hypothalamus and amygdala. By birth, this network has become sexually dimorphic in a cluster of aromatase neurons in the arcuate nucleus adjacent to kisspeptin neurons. We demonstrate that male arcuate aromatase neurons convert testosterone to estrogen to regulate kisspeptin neuron activity. We provide spatiotemporal information on aromatase neuronal network development and highlight a novel mechanism whereby aromatase neurons regulate the activity of distinct neuronal populations expressing estrogen receptors.SIGNIFICANCE STATEMENTSex steroid hormones, such as estradiol, are important regulators of neural circuits controlling reproductive physiology in the brain. Embryonic kisspeptin neurons in the hypothalamus express steroid hormone receptors, suggesting hormone action on these cellsin utero. Whether neurosteroids are locally produced in the brain and impinge onto reproductive neural circuitry is insufficiently understood. To address this question, we analyzed aromatase expression, a key enzyme in estradiol synthesis, in mouse embryos and identified a network comprising ∼6000 neurons in the brain. By birth, this network has become sexually dimorphic in a cluster of aromatase neurons in the arcuate nucleus adjacent to kisspeptin neurons. We demonstrate that male aromatase neurons convert testosterone to estradiol to regulate kisspeptin neuron activity.

Brain injuries cause hemodynamic changes in several distant, spared areas from the lesion. Our objective was to better understand the neuronal correlates of this reorganization in awake, behaving female monkeys. We used reversible inactivation techniques to “injure” the primary motor cortex, while continuously recording neuronal activity of the ventral premotor cortex in the two hemispheres, before and after the onset of behavioral impairments. Inactivation rapidly induced profound alterations of neuronal discharges that were heterogeneous within each and across the two hemispheres, occurred during movements of either the affected or nonaffected arm, and varied during different phases of grasping. Our results support that extensive, and much more complex than expected, neuronal reorganization takes place in spared areas of the bihemispheric cortical network involved in the control of hand movements. This broad pattern of reorganization offers potential targets that should be considered for the development of neuromodulation protocols applied early after brain injury.SIGNIFICANCE STATEMENTIt is well known that brain injuries cause changes in several distant, spared areas of the network, often in the premotor cortex. This reorganization is greater early after the injury and the magnitude of early changes correlates with impairments. However, studies to date have used noninvasive brain imaging approaches or have been conducted in sedated animals. Therefore, we do not know how brain injuries specifically affect the activity of neurons during the generation of movements. Our study clearly shows how a lesion rapidly impacts neurons in the premotor cortex of both hemispheres. A better understanding of these complex changes can help formulate hypotheses for the development of new treatments that specifically target neuronal reorganization induced by lesions in the brain.

Focused ultrasound combined with circulating microbubbles (FUS+MB) can transiently enhance blood-brain barrier (BBB) permeability at targeted brain locations. Its great promise in improving drug delivery to the brain is reflected by a rapidly growing number of clinical trials using FUS+MB to treat various brain diseases. As the clinical applications of FUS+MB continue to expand, it is critical to have a better understanding of the molecular and cellular effects induced by FUS+MB to enhance the efficacy of current treatment and enable the discovery of new therapeutic strategies. Existing studies primarily focus on FUS+MB-induced effects on brain endothelial cells, the major cellular component of BBB. However, bioeffects induced by FUS+MB expand beyond the BBB to cells surrounding blood vessels, including astrocytes, microglia, and neurons. Together these cell types comprise the neurovascular unit (NVU). In this review, we examine cell-type-specific bioeffects of FUS+MB on different NVU components, including enhanced permeability in endothelial cells, activation of astrocytes and microglia, as well as increased intraneuron protein metabolism and neuronal activity. Finally, we discuss knowledge gaps that must be addressed to further advance clinical applications of FUS+MB.

A minimally invasive, microchip-based approach enables continuous long-term recording of brain neurovascular activity, heart rate, and head movement in freely behaving rodents. This approach can also be used for transcranial optical triggering of cortical activity in mice expressing channelrhodopsin. The system uses optical intrinsic signal recording to measure cerebral blood volume, which under baseline conditions is correlated with spontaneous neuronal activity. The arterial pulse and breathing can be quantified as a component of the optical intrinsic signal. Multi-directional head movement is measured simultaneously with a movement sensor. A separate movement tracking element through a camera enables precise mapping of overall movement within an enclosure. Data is processed by a dedicated single board computer, and streamed from multiple enclosures to a central server, enabling simultaneous remote monitoring and triggering in many subjects. One application of this system described here is the characterization of changes in of cerebral blood volume, heart rate and behaviour that occur with the sleep-wake cycle over weeks. Another application is optical triggering and recording of cortical spreading depression (CSD), the slowly propagated wave of neurovascular activity that occurs in the setting of brain injury and migraine aura. The neurovascular features of CSD are remarkably different in the awake vs. anaesthetized state in the same mouse. With its capacity to continuously and synchronously record multiple types of physiological and behavioural data over extended time periods in combination with intermittent triggering of brain activity, this inexpensive method has the potential for widespread practical application in rodent research. KEY POINTS: Recording and triggering of brain activity in mice and rats has typically required breaching the skull, and experiments are often performed under anaesthesia A minimally invasive microchip system enables continuous recording and triggering of neurovascular activity, and analysis of heart rate and behaviour in freely behaving rodents over weeks This system can be used to characterize physiological and behavioural changes associated with the sleep-wake cycle over extended time periods This approach can also be used with mice expressing channelrhodopsin to trigger and record cortical spreading depression (CSD) in freely behaving subjects. The neurovascular responses to CSD are remarkably different under anaesthesia compared with the awake state. The method is inexpensive and straightforward to employ at a relatively large scale. It enables translational investigation of a wide range of physiological and pathological conditions in rodent models of neurological and systemic diseases.

The posterior parietal cortex (PPC) is important for visuospatial attention. The primate PPC shows functional differentiation such that dorsal areas are implicated in top–down, controlled attention, and ventral areas are implicated in bottom–up, stimulus-driven attention. Whether the rat PPC also shows such functional differentiation is unknown. Here, we address this open question using functional neuroanatomy and in vivo electrophysiology. Using conventional tract-tracing methods, we examined connectivity with other structures implicated in visuospatial attention including the lateral posterior nucleus of the thalamus (LPn) and the postrhinal cortex (POR). We showed that the LPn projects to the entire PPC, preferentially targeting more ventral areas. All parts of the PPC and POR are reciprocally connected with the strongest connections evident between ventral PPC and caudal POR. Next, we simultaneously recorded neuronal activity in dorsal and ventral PPC as rats performed a visuospatial attention (VSA ) task that engages in both bottom–up and top–down attention. Previously, we provided evidence that the dorsal PPC is engaged in multiple cognitive process including controlled attention (Yang et al. 2017). Here, we further showed that ventral PPC cells respond to stimulus onset more rapidly than dorsal PPC cells, providing evidence for a role in stimulus-driven, bottom–up attention.

Astrocytes play key roles in regulating multiple aspects of neuronal function from invertebrates to humans and display Ca2+ fluctuations that are heterogeneously distributed throughout different cellular microdomains. Changes in Ca2+ dynamics represent a key mechanism for how astrocytes modulate neuronal activity. An unresolved issue is the origin and contribution of specific glial Ca2+ signaling components at distinct astrocytic domains to neuronal physiology and brain function. The Drosophila model system offers a simple nervous system that is highly amenable to cell-specific genetic manipulations to characterize the role of glial Ca2+ signaling. Here we identify a role for ER store-operated Ca2+ entry (SOCE) pathway in perineurial glia (PG), a glial population that contributes to the Drosophila blood-brain barrier. We show that PG cells display diverse Ca2+ activity that varies based on their locale within the brain. Ca2+ signaling in PG cells does not require extracellular Ca2+ and is blocked by inhibition of SOCE, Ryanodine receptors, or gap junctions. Disruption of these components triggers stimuli-induced seizure-like episodes. These findings indicate that Ca2+ release from internal stores and its propagation between neighboring glial cells via gap junctions are essential for maintaining normal nervous system function.

Myelination is crucial for the development and maintenance of axonal integrity, especially fast axonal action potential conduction. There is increasing evidence that glutamate signaling and release through neuronal activity modulates the myelination process. In this study, we examine the effect of manipulating glutamate signaling on myelination of oligodendrocyte (OL) lineage cells and their development in zebrafish (zf). We use the "intensity-based glutamate-sensing fluorescent reporter" (iGluSnFR) in the zf model (both sexes) to address the hypothesis that glutamate is implicated in regulation of myelinating OLs. Our results show that glial iGluSnFR expression significantly reduces OL lineage cell number and the expression of myelin markers in larvae (zfl) and adult brains. The specific glutamate receptor agonist, L-AP4, rescues this iGluSnFR effect by significantly increasing the expression of the myelin-related genes, plp1b and mbpa, and enhances myelination in L-AP4-injected zfl compared to controls. Furthermore, we demonstrate that degrading glutamate using Glutamat-Pyruvate Transaminase (GPT) or the blockade of glutamate reuptake by L-trans-pyrrolidine-2,4-dicarboxylate (PDC) significantly decreases myelin-related genes and drastically declines myelination in brain ventricle-injected zfl. Moreover, we found that myelin-specific ClaudinK (CldnK) and 36K protein expression is significantly decreased in iGluSnFR-expressing zfl and adult brains compared to controls. Taken together, this study confirms that glutamate signaling is directly required for the preservation of myelinating OLs and for the myelination process itself. These findings further suggest that glutamate signaling may provide novel targets to therapeutically boost remyelination in several demyelinating diseases of the CNS.

For over a decade, neuroimaging and brain stimulation studies have investigated neural mechanisms of third-party punishment, a key instrument for social norms enforcement. However, the neural dynamics underlying these mechanisms are still unclear. Previous electroencephalographic studies on third-party punishment have shown that inter-brain connectivity is linked to punishment behavior. However, no clear evidence was provided regarding whether the effect of inter-brain connectivity on third-party punishment is mediated by local neuronal states. In this study, we further investigate whether resting-state neuronal activity in the alpha frequency range can predict individual differences in third-party punishment. More specifically, we show that the global resting-state connectivity between the right dorsolateral prefrontal and right temporo-parietal regions is negatively correlated with the level of third-party punishment. Additionally, individuals with stronger local resting-state long-range temporal correlations in the right temporo-parietal cortices demonstrated a lower level of third-party punishment. Thus, our results further support the idea that global and local neuronal dynamics can contribute to individual differences in third-party punishment.