Modulation Of Neurons Research Articles

Impact of chronic ethanol exposure on inhibitory modulation of CRF1-expressing neurons in the mouse ventral bed nucleus of the stria terminalis

Impact of chronic ethanol exposure on inhibitory modulation of CRF1-expressing neurons in the mouse ventral bed nucleus of the stria terminalis

Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer's disease.

Cerebrovascular dysregulation is a hallmark of Alzheimer's disease (AD), but the changes that occur in specific cell types have not been fully characterized. Here, we profile single-nucleus transcriptomes in the human cerebrovasculature in six brain regions from 220 individuals with AD and 208 age-matched controls. We annotate 22,514 cerebrovascular cells, including 11 subtypes of endothelial, pericyte, smooth muscle, perivascular fibroblast and ependymal cells. We identify 2,676 differentially expressed genes in AD, including downregulation of PDGFRB in pericytes, and of ABCB1 and ATP10A in endothelial cells, and validate the downregulation of SLC6A1 and upregulation of APOD, INSR and COL4A1 in postmortem AD brain tissues. We detect vasculature, glial and neuronal coexpressed gene modules, suggesting coordinated neurovascular unit dysregulation in AD. Integration with AD genetics reveals 125 AD differentially expressed genes directly linked to AD-associated genetic variants. Lastly, we show that APOE4 genotype-associated differences are significantly enriched among AD-associated genes in capillary and venule endothelial cells, as well as subsets of pericytes and fibroblasts.

Human Alzheimer’s postmortem raphe brain heterogeneity: Single cell RNAseq 10X genomics approach

AbstractBackgroundThe complexity of subcortical brain remains unexplored due to complex neuronal structure and heterogeneity of neuronal populations in the brain. Raphe brain regulates multiple physiological events like stress, memory, feeding, sleep, movement, balance, and many others. ere we present the single cell RNAsec (scRNAseq) analysis of raphe tissue from the postmortem brains of Alzheimer’s disease Braak Stages VI and control subjects.MethodPostmortem raphe brains acquired from NIH‐NeuroBioBank. Intact cells were collected using Cell Raft AIR System. Single cell suspension of neurons and synthesized cDNA and normalized cDNA using library preparation. The samples were processed in NextGen v3‐1 using 10X Genomics Chromium system. The library was sequenced ± 200 million PE150 reads /sample on Illumina Novaseq. The sequences were mapped against GRCh38 using Cell ranger v6.1.ResultThe data will be analyzed using 10X genomics cell ranger and Loup Browser tools. Further functional genomics tool DAVID ) v6.8 and ( IPA ) will be used to analyze heterogeneity of raphe brain and various presynaptic neuronal modulation in 1. AD and control, 2. AD and control males and 3. AD and control females. The most astringent analysis of data showed 5% mitochondrial genes, . We will also analyze the therapeutic targets and biological pathways. Heterogeneity of raphe and genes triggered in AD pathology will also be investigated.ConclusionThe raphe connectivity to Alzheimer’s disease and other dementias was a hot‐topic in 1980s research and somehow lost interest in the last 2 decades. The concept of serotonin neuromodulation evolves in recent years due to new concept of serotonin connecting intracellular and intracellular neuromodulation, use of serotonin drug targets in behavior alterations in dementia and early depression and aggression might be a causal factor to neurodegenerative onset much before classic pathologies of the disease appear. Our study will reveal the heterogenous neuronal population in complex raphe region of the brain and how the microenvironment changes neurotransmission in the forebrain. We will present extensive analysis on neuronal population of raphe and its role in AD and healthy subjects. The results will be a AD and ADRD models to pinpoint the changes in 5HTsynthesis and neuromodulation to forebrain and cerebellum.

Meta-model of Human Recognition-behavioral Adaptation System

Scientific modeling is a syllogistic system of definitive premise, sound inference and consistent explanation to understand, define, quantify, visualize or simulate feature of the target. Single-model is defined to an informative representation for identifying a property of a target object/phenomenon, and meta-model integrates the relevant single-models to explain phenomenological realities. Human recognition-behavioral adaptation is an information-metabolism system to maintain homeostasis of human-self, and that has been investigated in neurological, psychiatric and psychological aspects. I analyzed human recognition-behavioral adaptation-system via scientific modeling. Neurological meta-model of human recognition-behavioral adaptation system was synthesized as complex-network of the functional neuronal modules, and the meta-model was integrated to Mentality-model in the psychiatric aspect, and to Personality-model in the psychological aspect. The integrated meta-models successfully explained phenomenological realities in the aspects. From the above, I comprehended that the meta-model of human recognition-behavioral adaptation-system has been developed to Biopsychosocial model integrating the biological, psychological and socio-environmental factors.

Spatial Attention Modulates Neuronal Interactions between Simple and Complex Cells in V1.

Visual perception is profoundly modulated by spatial attention, which can selectively prioritize goal-related information. Previous studies found spatial attention facilitated the efficacy of neuronal communication between visual cortices with hierarchical organizations. In the primary visual cortex (V1), there is also a hierarchical connection between simple (S) and complex (C) cells. We wonder whether and how spatial attention modulates neuronal communication within V1, especially for neuronal pairs with heterogeneous visual input. We simultaneously recorded the pairs' activity from macaque monkeys when they performed a spatial-attention-involved task, then applied likelihood-based Granger causality analysis to explore attentional modulation of neuronal interactions. First, a significant attention-related decrease in Granger causality was found in S-C pairs, which primarily displayed in the S-to-C feedforward connection. Second, the interaction strength of the feedforward connection was significantly higher than that of the feedback under attend toward (AT) conditions. Although information flow did not alter as the attentional focus shifted, the strength of communications between target- and distractor-stimuli-covered neurons differed only when attending to complex cells' receptive fields (RFs). Furthermore, pairs' communications depended on the attentional modulation of neurons' firing rates. Our findings demonstrate spatial attention does not induce specific information flow but rather amplifies directed communication within V1.

Arousal and locomotion differently modulate activity of somatostatin neurons across cortex.

Arousal powerfully influences cortical activity, in part by modulating local inhibitory circuits. Somatostatin-expressing inhibitory interneurons (SOM) are particularly well-situated to shape local population activity in response to shifts in arousal, yet the relationship between arousal state and SOM activity has not been characterized outside of sensory cortex. To determine whether SOM activity is similarly modulated by behavioral state across different levels of the cortical processing hierarchy, we compared the behavioral modulation of SOM neurons in auditory cortex (AC), a primary sensory region, and posterior parietal cortex (PPC), an association-level region of cortex, in mice. Behavioral state modulated activity differently in AC and PPC. In PPC, transitions to high arousal were accompanied by large increases in activity across the full PPC neural population, especially in SOM neurons. In AC, arousal transitions led to more subtle changes in overall activity, as individual SOM and Non-SOM neurons could be either positively or negatively modulated during transitions to high arousal states. The coding of sensory information in population activity was enhanced during periods of high arousal in AC, but not PPC. Our findings suggest unique relationships between activity in local circuits and arousal across cortex, which may be tailored to the roles of specific cortical regions in sensory processing or the control of behavior.Significance statementThe effects of arousal on brain networks are profound, but vary across regions. Somatostatin neurons may carry out some of the effects of arousal on local network activity in sensory cortex, by modulating response gain and decorrelating population activity. However, SOM neurons have not been well studied outside of sensory cortex, and so it is unknown whether SOM neurons are similarly affected by shifts in brain state throughout the cortex. Here, we have revealed specialization in the relationship between arousal and activity in SOM neurons that could contribute to the diversity of arousal-related impacts on local computation across cortical regions.

Memristor-Based Neural Network Circuit With Multimode Generalization and Differentiation on Pavlov Associative Memory

Most of the classical conditioning laws implemented by existing circuits are involved in learning and forgetting between only three neurons, and the problems between multiple neurons are not considered. In this article, a multimode generalization and differentiation circuit for the Pavlov associative memory is proposed based on memristors. The designed circuit is mainly composed of voltage control modules, synaptic neuron modules, and inhibition modules. The secondary differentiation is accomplished through the process of associative learning and forgetting among multiple neurons. The process of multiple generalization and differentiation is realized based on the nonvolatility and thresholding properties of memristors. The extinction inhibition and differentiation inhibition in forgetting is considered through the inhibition modules. The Pavlov associative memory neural network with multimodal generalization and differentiation may provide a reference for the further development of brain-like intelligence.

Movement Disorders Associated with Cerebral Artery Stenosis: A Nationwide Study (P13-11.003)

<h3>Objective:</h3> We aimed to investigate the clinical characteristics of movement disorders (MD) associated with cerebral artery stenosis (CAS). <h3>Background:</h3> Studies of secondary MD caused by cerebrovascular diseases have primarily focused on post-stroke MD. However, MD can also result from CAS without clinical manifestations of stroke. <h3>Design/Methods:</h3> A nationwide multi-center retrospective analysis was performed based on the data from patients with CAS-associated MDs from MD specialized clinics in South Korea, available between January 1999 and September 2019. CAS was defined as the &gt; 50% luminal stenosis of the major cerebral arteries. The association between the MD and CAS was determined by MD specialists using predefined clinical criteria. The collected clinical information included baseline demographics, features of MD, characteristics of CAS, treatment, and outcomes of MD. Statistical analyses were performed to identify factors associated with the outcomes of MD. <h3>Results:</h3> The data from a total of 81 patients with CAS-associated MD were analyzed. The mean age of MD onset was 60.5 ± 19.7 years. Chorea was the most common MD (57%), followed by tremor/limb-shaking, myoclonus, and dystonia. Atherosclerosis was the most common etiology of CAS (78%), with the remaining cases attributed to moyamoya disease. Relative to patients with atherosclerosis, those with moyamoya disease developed MD at a younger age (p &lt; 0.001) and had a more chronic mode of onset (p = 0.001) and less acute ischemic lesion (p = 0.021). Eight patients who underwent surgical treatment for CAS showed positive outcomes. Patients with acute onset of MD had a better outcome than those with subacute-to-chronic onset of MD (p = 0.008). <h3>Conclusions:</h3> This study highlights the spectrum of CAS-associated with MD across the country. A progressive, age-dependent functional neuronal modulation in the basal ganglia due to CAS may underlie this condition. <b>Disclosure:</b> Dr. Chung has nothing to disclose. Dr. Choi has nothing to disclose. Prof. Oh has nothing to disclose. Ho-Sung Ryu has nothing to disclose. Sooyeoun You has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Park has nothing to disclose.

Noninvasive ultrasound stimulation to treat myocarditis through splenic neuro-immune regulation

BackgroundThe cholinergic anti-inflammatory pathway (CAP) has been widely studied to modulate the immune response. Current stimulating strategies are invasive or imprecise. Noninvasive low-intensity pulsed ultrasound (LIPUS) has become increasingly appreciated for targeted neuronal modulation. However, its mechanisms and physiological role on myocarditis remain poorly defined.MethodsThe mouse model of experimental autoimmune myocarditis was established. Low-intensity pulsed ultrasound was targeted at the spleen to stimulate the spleen nerve. Under different ultrasound parameters, histological tests and molecular biology were performed to observe inflammatory lesions and changes in immune cell subsets in the spleen and heart. In addition, we evaluated the dependence of the spleen nerve and cholinergic anti-inflammatory pathway of low-intensity pulsed ultrasound in treating autoimmune myocarditis in mice through different control groups.ResultsThe echocardiography and flow cytometry of splenic or heart infiltrating immune cells revealed that splenic ultrasound could alleviate the immune response, regulate the proportion and function of CD4+ Treg and macrophages by activating cholinergic anti-inflammatory pathway, and finally reduce heart inflammatory injury and improve cardiac remodeling, which is as effective as an acetylcholine receptor agonists GTS-21. Transcriptome sequencing showed significant differential expressed genes due to ultrasound modulation.ConclusionsIt is worth noting that the ultrasound therapeutic efficacy depends greatly on acoustic pressure and exposure duration, and the effective targeting organ was the spleen but not the heart. This study provides novel insight into the therapeutic potentials of LIPUS, which are essential for its future application.Graphical

Microglia cause structural remodeling of noradrenergic axon in the trigeminal spinal subnucleus caudalis after infraorbital nerve injury in rats

The dysfunction of descending noradrenergic (NAergic) modulation in second-order neurons has long been observed in neuropathic pain. In clinical practice, antidepressants that increase noradrenaline levels in the synaptic cleft are used as first-line agents, although adequate analgesia has not been occasionally achieved. One of the hallmarks of neuropathic pain in the orofacial regions is microglial abnormalities in the trigeminal spinal subnucleus caudalis (Vc). However, until now, the direct interaction between descending NAergic system and Vc microglia in orofacial neuropathic pain has not been explored. We found that reactive microglia ingested the dopamine-β-hydroxylase (DβH)-positive fraction, NAergic fibers, in the Vc after infraorbital nerve injury (IONI). Major histocompatibility complex class I (MHC-I) was upregulated in Vc microglia after IONI. Interferon-γ (IFNγ) was de novo induced in trigeminal ganglion (TG) neurons following IONI, especially in C-fiber neurons, which conveyed to the central terminal of TG neurons. Gene silencing of IFNγ in the TG reduced MHC-I expression in the Vc after IONI. Intracisternal administration of exosomes from IFNγ-stimulated microglia elicited mechanical allodynia and a decrease in DβH in the Vc, which did not occur when exosomal MHC-I was knocked down. Similarly, in vivo MHC-I knockdown in Vc microglia attenuated the development of mechanical allodynia and a decrease in DβH in the Vc after IONI. These results show that microglia-derived MHC-I causes a decrease in NAergic fibers, culminating in orofacial neuropathic pain.

Exploring the Pathological Effect of Aβ42 Oligomers on Neural Networks in Primary Cortical Neuron Culture.

Alzheimer's disease (AD) is a multifactorial disorder that affects cognitive functioning, behavior, and neuronal properties. The neuronal dysfunction is primarily responsible for cognitive decline in AD patients, with many causal factors including plaque accumulation of Aβ42. Neural hyperactivity induced by Aβ42 deposition causes abnormalities in neural networks, leading to alterations in synaptic activity and interneuron dysfunction. Even though neuroimaging techniques elucidated the underlying mechanism of neural connectivity, precise understanding at the cellular level is still elusive. Previous multielectrode array studies have examined the neuronal network modulation in in vitro cultures revealing the relevance of ion channels and the chemical modulators in the presence of Aβ42. In this study, we investigated neuronal connectivity and dynamic changes using a high-density multielectrode array, particularly looking at network-wide parameter changes over time. By comparing the neuronal network between normal and Aβ42treated neuronal cultures, it was possible to discover the direct pathological effect of the Aβ42 oligomer altering the network characteristics. The detrimental effects of the Aβ42 oligomer included not only a decline in spike activation but also a qualitative impairment in neural connectivity as well as a disorientation of dispersibility. As a result, this will improve our understanding of how neural networks are modified during AD progression.

Optimal synchronization in pulse-coupled oscillator networks using reinforcement learning.

Spontaneous synchronization is ubiquitous in natural and man-made systems. It underlies emergent behaviors such as neuronal response modulation and is fundamental to the coordination of robot swarms and autonomous vehicle fleets. Due to its simplicity and physical interpretability, pulse-coupled oscillators has emerged as one of the standard models for synchronization. However, existing analytical results for this model assume ideal conditions, including homogeneous oscillator frequencies and negligible coupling delays, as well as strict requirements on the initial phase distribution and the network topology. Using reinforcement learning, we obtain an optimal pulse-interaction mechanism (encoded in phase response function) that optimizes the probability of synchronization even in the presence of nonideal conditions. For small oscillator heterogeneities and propagation delays, we propose a heuristic formula for highly effective phase response functions that can be applied to general networks and unrestricted initial phase distributions. This allows us to bypass the need to relearn the phase response function for every new network.

Top-down control of human motor thalamic neuronal activity during the auditory oddball task

The neurophysiology of selective attention in visual and auditory systems has been studied in animal models but not with single unit recordings in human. Here, we recorded neuronal activity in the ventral intermediate nucleus as well as the ventral oral anterior, and posterior nuclei of the motor thalamus in 25 patients with parkinsonian (n = 6) and non-parkinsonian tremors (n = 19) prior to insertion of deep brain stimulation electrodes while they performed an auditory oddball task. In this task, patients were requested to attend and count the randomly occurring odd or “deviant” tones, ignore the frequent standard tones and report the number of deviant tones at trial completion. The neuronal firing rate decreased compared to baseline during the oddball task. Inhibition was specific to auditory attention as incorrect counting or wrist flicking to the deviant tones did not produce such inhibition. Local field potential analysis showed beta (13–35 Hz) desynchronization in response to deviant tones. Parkinson’s disease patients off medications had more beta power than the essential tremor group but less neuronal modulation of beta power to the attended tones, suggesting that dopamine modulates thalamic beta oscillations for selective attention. The current study demonstrated that ascending information to the motor thalamus can be suppressed during auditory attending tasks, providing indirect evidence for the searchlight hypothesis in humans. These results taken together implicate the ventral intermediate nucleus in non-motor cognitive functions, which has implications for the brain circuitry for attention and the pathophysiology of Parkinson’s disease.

Vesicular Zinc Modulates Cell Proliferation and Survival in the Developing Hippocampus.

In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic vesicles by zinc transporter 3 (ZnT3), has extensive effects on neuronal signalling and modulation. Vesicular zinc-focused research has mainly been directed to its role in the hippocampus, particularly in adult neurogenesis. However, whether vesicular zinc is involved in modulating neurogenesis during the early postnatal period has been less studied. As a first step to understanding this, we used ZnT3 knockout (KO) mice, which lack ZnT3 and, thus, vesicular zinc, to evaluate cell proliferation at three different age points spanning postnatal development (P6, P14, and P28). The survival and the neuronal phenotype of these cells was also assessed in adulthood. We found that male ZnT3 KO mice exhibited lower rates of cell proliferation at P14, but a greater number of these cells survived to adulthood. Additionally, significantly more cells labelled on P6 survived to adulthood in male and female ZnT3 KO mice. We also found sex-dependent differences, whereby male mice showed higher levels of cell proliferation at P28, as well as higher levels of cell survival for P14-labelled cells, compared to female mice. However, female mice showed greater percentages of neuronal differentiation for P14-labelled cells. Finally, we found significant effects of age of BrdU injections on cell proliferation, survival, and neuronal differentiation. Collectively, our results suggest that the loss of vesicular zinc affects normal proliferation and survival of cells born at different age points during postnatal development and highlight prominent sex- and age-dependent differences. Our findings provide the foundation for future studies to further probe the role of vesicular zinc in the modulation of developmental neurogenesis.

Advances of H2S in Regulating Neurodegenerative Diseases by Preserving Mitochondria Function

Neurotoxicity is induced by different toxic substances, including environmental chemicals, drugs, and pathogenic toxins, resulting in oxidative damage and neurodegeneration in mammals. The nervous system is extremely vulnerable to oxidative stress because of its high oxygen demand. Mitochondria are the main source of ATP production in the brain neuron, and oxidative stress-caused mitochondrial dysfunction is implicated in neurodegenerative diseases. H2S was initially identified as a toxic gas; however, more recently, it has been recognized as a neuromodulator as well as a neuroprotectant. Specifically, it modulates mitochondrial activity, and H2S oxidation in mitochondria produces various reactive sulfur species, thus modifying proteins through sulfhydration. This review focused on highlighting the neuron modulation role of H2S in regulating neurodegenerative diseases through anti-oxidative, anti-inflammatory, anti-apoptotic and S-sulfhydration, and emphasized the importance of H2S as a therapeutic molecule for neurological diseases.

Self-aware artificial auditory neuron with a triboelectric sensor for spike-based neuromorphic hardware

Auditory organs can detect and process sounds with the help of the organ of Corti located in the cochlea. The energy efficiency of biological processing for an input sound signal is very high due to the spike-based auditory neurons in auditory organs. Here, inspired by the biological auditory system, a self-aware artificial auditory neuron module is constructed by serially connecting a triboelectric nanogenerator (TENG) and a bi-stable resistor (biristor). The TENG serves as a sound sensor and a current source to feed current input so as to awaken the biristor, which acts as a device-level neuron that is dissimilar to a traditional circuit-based neuron. The proposed self-aware artificial neuron module simultaneously detects the sound pressure level (SPL) and encodes it into a spike form, after which it transmits these data to an artificial synapse as an input neuron for a spiking neural network (SNN). Like an auditory organ, the spiking frequency of the bio-inspired artificial neuron increases when the SPL increases. In addition, the self-aware artificial auditory system with a single-layer perceptron (SLP) for SNN is demonstrated for musical pitch classification. This artificial auditory system is configured by combining two artificial auditory neuron modules and four metal-oxide-semiconductor field-effect transistor (MOSFET) synapses. The biristor neuron and the MOSFET synapse are structurally identical but electrically different. Two artificial auditory neuron modules correspond to two different frequencies. This artificial auditory system distinguishes two sounds from a piano. It also identifies two similar sounds from a cello and a violin. The proposed artificial SNN-based auditory system is advantageous for low power consumption due to the event-driven spiking transmission scheme. The improved energy efficiency with the SNN as described here is attributed to the self-aware sensing capability for sound signals. Therefore, the self-aware SNN auditory system given its low power consumption is promising for a remote sensor, a wireless sensor, and for an Internet of Things (IoT) sensor system.

Sexual dysfunction and motor disability in Parkinson’s disease: any link?

IntroductionParkinson’s disease (PD) is a chronic, neurodegenerative disorder leading to dopamine deficiency. Phenotypically, there is a wide spectrum of motor and non-motor symptoms (NMS). Among NMS, sexual dysfunction (SD) is one of the most disabling and crippling symptom. However, SD are usually neglected and underdiagnosed in PD patients.ObjectivesOur study aimed to estimate the effect of motor disability and the disease course on sexual dysfunction in PD patients.MethodsThis retrospective study included 42 patients (18 males and 24 females) from the department of neurology of the National Institute of Neurology Mongi Ben Hmida in Tunis, Tunisia, diagnosed with PD between 1999 and 2022. The diagnosis of PD was confirmed according to the Movement Disorder Society (MDS) diagnostic criteria of PD. The MDS Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor was used to estimate motor disability and Hoehn and Yahr (H&amp;Y) stage was used to rate disease severity. The SD of PD patients was measured by applying the sexual items of Scales for Outcomes in Parkinson’s Disease - Autonomic Dysfunction (SCOPA-AUT).ResultsSD was observed in only 11 patients (26.2%) with a sex-ratio of M/F = 1.2 and a mean age of 52 (between 40 and 72). The mean age of PD onset was 47. According to the MDS-UPDRS part III, 1 patient had a severe motor disorder (MDS-UPDRS&gt; 59), and according to the H&amp;Y scale, no patient had a severe stage of the disease. Nine patients had motor complications such as motor fluctuations and L-Dopa induced dyskinesia.The SD described by our patients were: women reported Vaginal Dryness (4 patients), with difficulties reaching an orgasm (3 patients); men reported erectile dysfunction (6 patients), and difficulties in reaching an orgasm (6 patients). Among these patients, 3 were treated for SD with Tadalafil (all males).In our study, no significant gender-related differences were found in scores related to SD in patients with PD. Neither the disease severity nor the motor disability was significantly associated to sexual disorders (respectively p=0.26 and p=0.12). Also, Motor complications induced by L-Dopa medication, assessed by the part IV of MDS-UPDRS scale, had no significant effect in the occurrence of SD in PD (p=0.78).ConclusionsSexual behavior has neuronal and hormonal modulation. Lack of dopamine seems to have an important role in the development of SD. However, it occurs independently of the disease severity and the motor disability. Thus, clinicians should be aware of the importance of assessing and treating such symptoms since the beginning of the disease.Disclosure of InterestNone Declared

Ultrasound modulation of neurons by sonogenetics

Focused ultrasound (FUS) can noninvasively deliver ultrasound energy to target any area in the whole brain with combined depth penetration and spatial focusing that cannot be achieved with other external stimulations. Sonogenetics, integrating focused ultrasound with genetic engineering, can achieve noninvasive control of neurons genetically modified with ultrasound-sensitive ion channels. Crucial to the development of sonogenetics has been the identification of ultrasound-sensitive probes to control neurons. FUS propagation through the tissue can generate mechanical and thermal effects within its focal region. This talk will present recent progress in the development of mechanosensitive and thermosensitive ion channels as sonogenetic probes. Recent success in using sonogenetics for noninvasive and cell-type-specific behavior control of freely moving mice will also be presented. This noninvasive and cell-type-specific neuromodulation approach has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders.

Neural correlates of cognitively controlled vocalizations in a corvid songbird

The neuronal basis of the songbird's song system is well understood. However, little is known about the neuronal correlates of the executive control of songbird vocalizations. Here, we record single-unit activity from the pallial endbrain region "nidopallium caudolaterale" (NCL) of crows that vocalize to the presentation of a visual go-cue but refrain from vocalizing during trials without a go-cue. We find that the preparatory activity of single vocalization-correlated neurons, but also of the entire population of NCL neurons, before vocal onset predicts whether or not the crows will produce an instructed vocalization. Fluctuations in baseline neuronal activity prior to the go-cue influence the premotor activity of such vocalization-correlated neurons and seemingly bias the crows' decision to vocalize. Neuronal response modulation significantly differs between volitional and task-unrelated vocalizations. This suggests that the NCL can take control over the vocal motor network during the production of volitional vocalizations in a corvid songbird.

Selective activation of cholinergic neurotransmission from the medial septal nucleus to hippocampal pyramidal neurones improves sepsis-induced cognitive deficits in mice

BackgroundSepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission in the hippocampus impairs memory function. We assessed real-time alterations of acetylcholine neurotransmission from the medial septal nucleus to the hippocampus, and explored whether sepsis-induced cognitive deficits can be relieved by activating upstream cholinergic projections. MethodLipopolysaccharide (LPS) injection or caecal ligation and puncture (CLP) was used to induce sepsis and associated neuroinflammation in wild-type and mutant mice. Adeno-associated viruses for calcium and acetylcholine imaging, and for optogenetic and chemogenetic modulation of cholinergic neurones were injected into the hippocampus or medial septum, and a 200-μm-diameter optical fibre was implanted to collect acetylcholine and calcium signals. Cholinergic activity of the medial septum was manipulated and combined with cognitive assessment after LPS injection or CLP. ResultsIntracerebroventricular LPS injection reduced postsynaptic acetylcholine (from 0.146 [0.001] to 0.0047 [0.0005]; p=0.004) and calcium (from 0.0236 [0.0075] to 0.0054 [0.0026]; p=0.0388) signals in hippocampal Vglut2-positive glutamatergic neurones, whereas optogenetic activation of cholinergic neurones in the medial septum reversed LPS-induced reductions in these two signals. Intraperitoneal LPS injection decreased acetylcholine concentration in the hippocampus (476 [20] pg ml−1 to 382 [14] pg ml−1; p=0.0001). Reduction in long-term potentiation (238 [23] % to 150 [12] %; p=0.0082) and enhancement of hippocampal pyramidal neurone action potential frequency (5.8 [1.5] Hz to 8.2 [1.8] Hz; p=0.0343) were relieved, and neurocognitive performance was improved by chemogenetic activation of cholinergic innervation of the hippocampus 3 days after LPS injection in septic mice. ConclusionsSystemic or local LPS reduced cholinergic neurotransmission from the medial septum to hippocampal pyramidal neurones, and their selective activation alleviated defects in hippocampal neuronal function and synaptic plasticity and ameliorated memory deficits in sepsis model mice through enhanced cholinergic neurotransmission. This provides a basis for targeting cholinergic signalling to the hippocampus in sepsis-induced encephalopathy.