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The performance of neuromorphic computing (NC) in executing data-intensive artificial intelligence tasks relies on hardware network structure and information processing behavior mimicking neural networks in the human brain. The functionalities of synapses and neurons, the key components in neural networks, have been widely pursued in memristor systems. Nevertheless, the realization of neuronal functionalities in a single memristor remains challenging. By theoretical modeling, here we propose asymmetric ferroelectric tunneling junction (AFTJ) as a potential platform to realize neuronal functionalities. The volatility, a necessary property for a memristor to implement a neuron device, is enhanced by the co-effect of polarization asymmetry and Joule heating. The simulated polarization reversal dynamics of the AFTJ memristor under trains of electric pulses reproduces the leaky integrate-and-fire functionality of spiking neurons. Interestingly, multiple spiking behaviors are found by modulating the pulse width and interval of trains of electric pulses, which has not yet been reported in ferroelectric neuron. The influences of several key factors on the neuronal functionalities of AFTJ are further discussed. Our study provides a novel design scheme for ferroelectric neuron devices and inspires further explorations of ferroelectric devices in neuromorphic computing. [ABSTRACT FROM AUTHOR]

Anhedonia, the diminished drive to seek, value, and learn about rewards, is a core feature of major depressive disorder1-3. The neural underpinnings of anhedonia and how this emotional state drives behaviour remain unclear. Here we investigated the neural code of anhedonia by taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, whereas others remain resilient. By performing high-density electrophysiology to record neural activity patterns in the basolateral amygdala (BLA) and ventral CA1 (vCA1), we identified neural signatures of susceptibility and resilience. When mice actively sought rewards, BLA activity in resilient mice showed robust discrimination between reward choices. By contrast, susceptible mice exhibited a rumination-like signature, in which BLA neurons encoded the intention to switch or stay on a previously chosen reward. Manipulation of vCA1 inputs to the BLA in susceptible mice rescued dysfunctional neural dynamics, amplified dynamics associated with resilience, and reversed anhedonic behaviour. Finally, when animals were at rest, the spontaneous BLA activity of susceptible mice showed a greater number of distinct neural population states. This spontaneous activity allowed us to decode group identity and to infer whether a mouse had a history of stress better than behavioural outcomes alone. This work reveals population-level neural dynamics that explain individual differences in responses to traumatic stress, and suggests that modulating vCA1-BLA inputs can enhance resilience by regulating these dynamics.

The hippocampal CA3 subregion is a densely connected recurrent circuit that supports memory by generating and storing sequential neuronal activity patterns that reflect recent experience. While theta phase precession is thought to be critical for generating sequential activity during memory encoding, the circuit mechanisms that support this computation across hippocampal subregions are unknown. By analyzing CA3 network activity in the absence of each of its theta-modulated external excitatory inputs, we show necessary and unique contributions of the dentate gyrus (DG) and the medial entorhinal cortex (MEC) to phase precession. DG inputs are essential for preferential spiking of CA3 cells during late theta phases and for organizing the temporal order of neuronal firing, while MEC inputs sharpen the temporal precision throughout the theta cycle. A computational model that accounts for empirical findings suggests that the unique contribution of DG inputs to theta-related spike timing is supported by targeting precisely timed inhibitory oscillations. Our results thus identify a novel and unique functional role of the DG for sequence coding in the CA3 circuit.

This contribution is part of the special issue on the Hippocampus focused on personal histories of advances in knowledge on the hippocampus and related structures. An account is offered of the authors role in the development of neural ensemble recording: stereo recording (stereotrodes, tetrodes) and the use of this approach to search for evidence of Hebbs cell assemblies and phase sequences, the holy grail of the neuroscience of learning and memory.

Corticotropin-releasing hormone (CRH) signaling through its cognate receptors, CRHR1 and CRHR2, contributes to diverse stress-related functions in the mammalian brain. Whereas CRHR2 is predominantly expressed in choroid plexus and blood vessels, CRHR1 is abundantly expressed in neurons in discrete brain regions, including the neocortex, hippocampus and nucleus accumbens. Activation of CRHR1 influences motivated behaviors, emotional states, and learning and memory. However, it is unknown whether alterations in CRHR1 signaling contribute to aberrant motivated behaviors observed, for example, in stressful contexts. These questions require tools to manipulate CRHR1 selectively. Here we describe and validate a novel Crhr1-FlpO mouse. Using bacterial artificial chromosome (BAC) transgenesis, we engineered a transgenic mouse that expresses FlpO recombinase in CRHR1-expressing cells. We used two independent methods to assess the specificity of FlpO to CRHR1-expressing cells. First, we injected Crhr1-FlpO mice with Flp-dependent viruses expressing fluorescent reporter molecules. Additionally, we crossed the Crhr1-FlpO mouse with a transgenic Flp-dependent reporter mouse. CRHR1 and reporter molecules were identified using immunocytochemistry and visualized via confocal microscopy in several brain regions in which CRHR1 expression and function is established. Expression of Flp-dependent viral constructs was highly specific to CRHR1-expressing cells in all regions examined (over 90% co-localization). In accord, robust and specific expression of the Flp-dependent transgenic reporter was observed in a reporter mouse, recapitulating endogenous CRHR1 expression. The Crhr1-FlpO mouse enables selective genetic access to CRHR1-expressing cells within the mouse brain. When combined with Cre-lox or site-specific recombinases, the mouse facilitates intersectional manipulations of CRHR1-expressing neurons.

Astrocytes undergo morphological and functional alterations as they switch from a quiescent to a reactive state in the process known as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function. Astrocyte reactivity is accompanied by mitochondrial network fragmentation, a reduction in mitochondrial respiratory activity, lipid droplet accumulation, and changes in the secretory profile of astrocytes, among other phenotypical changes. This process affects their interaction with surrounding nerve cells, such as microglia and neurons, promoting a neuroinflammatory response that affects diverse processes, such as pain sensitization and neurodegeneration. This process and astrocyte response can be reversed with mitochondria-targeted metabolic reprogramming approaches. [Display omitted] In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system. Although astrocytes are typically considered to exhibit low mitochondrial respiratory chain activity, they possess a noteworthy mitochondrial network. Interestingly, both the morphology and activity of these organelles change following glial reactivity. Despite receiving less attention compared to studies on neuronal mitochondria, recent studies indicate that mitochondria play a crucial role in driving the transition of astrocytes from a quiescent to a reactive state in various neurological disorders. Notably, stimulating mitochondria in astrocytes has been shown to reduce damage associated with the neurodegenerative disease amyotrophic lateral sclerosis. Here, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage. In this review, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage. [ABSTRACT FROM AUTHOR]

Fast instinctive responses to environmental stimuli can be crucial for survival but are not always optimal. Animals can adapt their behavior and suppress instinctive reactions, but the neural pathways mediating such ethologically relevant forms of learning remain unclear. We found that posterolateral higher visual areas (plHVAs) are crucial for learning to suppress escapes from innate visual threats through a top-down pathway to the ventrolateral geniculate nucleus (vLGN). plHVAs are no longer necessary after learning; instead, the learned behavior relies on plasticity within vLGN populations that exert inhibitory control over escape responses. vLGN neurons receiving input from plHVAs enhance their responses to visual threat stimuli during learning through endocannabinoid-mediated long-term suppression of their inhibitory inputs. We thus reveal the detailed circuit, cellular, and synaptic mechanisms underlying experience-dependent suppression of fear responses. [ABSTRACT FROM AUTHOR]

In Huntington's disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG) n in the huntingtin (HTT) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat's length alongside genome-wide RNA expression. We found that the HTT CAG repeat expands somatically from 40–45 to 100–500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150–500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene and that HD pathogenesis is a DNA process for almost all of a neuron's life. [Display omitted] • The HD-causing CAG repeat expands somatically in HD-vulnerable neurons • Over decades, the unstable alleles expand to more than 10 times their initial length • The CAG repeat becomes toxic after expanding beyond 150 CAGs • HD pathogenesis is a DNA-repeat expansion process for almost all of a neuron's life Single-cell measurement of the Huntington's disease-causing CAG repeat reveals that somatic expansion of this repeat drives pathological changes in neurons, providing insights into disease progression, with implications for therapeutics in HD and potentially other DNA-repeat expansion disorders. [ABSTRACT FROM AUTHOR]

We study large deviations in the context of stochastic gradient descent for one-hidden-layer neural networks with quadratic loss. We derive a quenched large deviation principle, where we condition on an initial weight measure, and an annealed large deviation principle for the empirical weight evolution during training when letting the number of neurons and the number of training iterations simultaneously tend to infinity. The weight evolution is treated as an interacting dynamic particle system. The distinctive aspect compared to prior work on interacting particle systems lies in the discrete particle updates, simultaneously with a growing number of particles. [ABSTRACT FROM AUTHOR]

Archerfish hunt by shooting a jet of water at aerial targets, a behavior used to study their visual processing by presenting a set of images on a screen above the water tank and observing the behavioral response. Building on this unique behavior, it was recently shown that archerfish can be trained to distinguish between different object categories by generalizing from examples. Analysis of the archerfish's behavior revealed that the fish visual system relies on a small set of visual features for categorization and is more sensitive to object contours than to textures. To understand the neural basis of this object recognition, we investigated the neural representation of features and objects in the archerfish optic tectum using recording of single cells. We found that, although the optic tectum is an early stage of visual processing, a small population of neurons in this region contains information about the object category. This contrasts with the primate visual system, where the representation of objects emerges only at later stages of visual processing. These results suggest that early-stage feature extraction and object categorization in archerfish might represent a form of specialized visual processing. This contributes to a broader understanding of visual processing across taxa. [ABSTRACT FROM AUTHOR]

Animals construct diverse behavioral repertoires by moving a limited number of body parts with varied kinematics and patterns of coordination. There is evidence that distinct movements can be generated by changes in activity dynamics within a common pool of motoneurons or by selectively engaging specific subsets of motoneurons in a task-dependent manner. However, in most cases, we have an incomplete understanding of the patterns of motoneuron activity that generate distinct actions and of how upstream premotor circuits select and assemble such motor programs. In this study, we used two closely related but kinematically distinct types of saccadic eye movement in larval zebrafish as a model to examine circuit control of movement diversity. In contrast to the prevailing view of a final common pathway, we found that in the oculomotor nucleus, distinct subsets of motoneurons were engaged for each saccade type. This type-specific recruitment was topographically organized and aligned with ultrastructural differences in motoneuron morphology and afferent synaptic innervation. Medially located motoneurons were active for both saccade types, and circuit tracing revealed a type-agnostic premotor pathway that appears to control their recruitment. By contrast, a laterally located subset of motoneurons was specifically active for hunting-associated saccades and received premotor input from pretectal hunting command neurons. Our data support a model in which generalist and action-specific premotor pathways engage distinct subsets of motoneurons to elicit varied movements of the same body part that subserve distinct behavioral functions. [Display omitted] • Subsets of extraocular motoneurons control two types of adducting saccades • Recruitment of medial rectus motoneurons is controlled by distinct synaptic inputs • Parallel premotor pathways recruit motoneuron subsets in a context-specific manner • Forebrain hunting commands directly interface onto hunting-specialized motoneurons Dowell et al. discover that two kinematically distinct types of saccadic eye movement are controlled by specific subsets of extraocular motoneurons. Parallel type-specific and type-agnostic premotor pathways differentially engage motoneuron subsets during visual exploration and hunting. [ABSTRACT FROM AUTHOR]

It has long been a decades-old dogma that image perception is mediated solely by rods and cones, while intrinsically photosensitive retinal ganglion cells (ipRGCs) are responsible only for non-image-forming vision, such as circadian photoentrainment and pupillary light reflexes. Surprisingly, we discovered that ipRGC activation enhances the orientation selectivity of layer 2/3 neurons in the primary visual cortex (V1) of mice by both increasing preferred-orientation responses and narrowing tuning bandwidth. Mechanistically, we found that the tuning properties of V1 excitatory and inhibitory neurons are differentially influenced by ipRGC activation, leading to a reshaping of the excitatory/inhibitory balance that enhances visual cortical orientation selectivity. Furthermore, light activation of ipRGCs improves behavioral orientation discrimination in mice. Importantly, we found that specific activation of ipRGCs in human participants through visual spectrum manipulation significantly enhances visual orientation discriminability. Our study reveals a visual channel originating from "non-image-forming photoreceptors" that facilitates visual orientation feature perception. [Display omitted] • IpRGCs activation improves mouse V1 L2/3 orientation selectivity • IpRGCs differently modulate V1 L2/3 excitatory/inhibitory neurons' orientation tuning • IpRGCs enhance orientation discriminability in mouse and human Using two-photon and multi-channel recordings from mouse primary visual cortex V1, Shi, Zhang, et al. demonstrate that intrinsically photosensitive retinal ganglion cells improve V1 orientation selectivity by differentially modulating excitatory and inhibitory neurons. This modulation by ipRGCs ultimately improves orientation discrimination in both mice and humans. [ABSTRACT FROM AUTHOR]

Introduction: Melanin-concentrating hormone (MCH) neurons are essential regulators of energy and glucose homeostasis, sleep–wake behaviors, motivation, learning and memory. These neurons are anatomically distributed across the medial (MH) and lateral hypothalamus (LH), and the adjacent zona incerta (ZI), which may represent functional subgroups with distinct connectivity with different brain regions. Furthermore, MCH neurons can be classified according to co-expression of neuropeptides, such as cocaine and amphetamine- regulated transcript (CART). Methods: To identify functional similarities and differences of MCH subpopulations, we characterized their intrinsic electrophysiological properties using whole cell current clamp recording on acute brain slices from male and female mice. Results: MCH neurons were classified into subgroups according to their anatomical localization in three MCH-rich brain areas: MH, LH and ZI. Among the three brain regions, ZI MCH neurons were the least excitable while LH MCH neurons were the most excitable. Furthermore, grouping MCH neurons according to CART co-expression revealed that MCH/CART− cells are uniquely depolarized and excitable, and display H-currents. These MCH/CART− cells were mainly found in the LH, which may in part explain why LH MCH neurons are more excitable. While some sex differences were found, the majority of parameters investigated were not different. Discussion: Our results suggest that MCH/CART− cells are electrophysiologically distinct, whereas MCH/CART+ cells are largely similar despite their diffuse distribution in the hypothalamus. It is therefore a combination of intrinsic electrophysiological properties and neurochemical identities, in addition to anatomy and connectivity that are likely to be critical in defining functional subpopulations of MCH neurons. [ABSTRACT FROM AUTHOR]

The successful pursuit of future rewards requires forming an internal goal, followed by planning, decision-making, and progress-tracking over multiple steps. The initial step—forming goals and the plans for obtaining them—involves the subjective valuation of an anticipated reward, considering both the reward's properties and associated delay and physical-effort costs. Recent findings indicate individuals similarly evaluate cognitive effort over time (Johnson and Most, 2023). Success and failure in these processes have been linked to differential life outcomes and psychiatric conditions. Here we review evidence from single-neuron recordings and neuroimaging studies that implicate the amygdala—a brain structure long associated with cue-reactivity and emotion—in decision-making and the planned pursuit of future rewards (Grabenhorst et al., 2012, 2016, 2019, 2023;Hernadi et al., 2015;Zangemeister et al., 2016). The main findings are that, in behavioral tasks in which future rewards can be pursued through planning and stepwise decision-making, amygdala neurons prospectively encode the value of anticipated rewards and related behavioral plans. Moreover, amygdala neurons predict the stepwise choices to pursue these rewards, signal progress toward goals, and distinguish internally generated (i.e., self-determined) choices from externally imposed actions. Importantly, amygdala neurons integrate the subjective value of a future reward with delay and effort costs inherent in pursuing it. This neural evidence identifies three key computations of the primate amygdala that underlie the pursuit of future rewards: (1) forming a self-determined internal goal based on subjective reward-cost valuations, (2) defining a behavioral plan for obtaining the goal, (3) executing this plan through stepwise decision-making and progress-tracking. Based on this framework, we suggest that amygdala neurons constitute vulnerabilities for dysfunction that contribute to maladaptive reward pursuit in psychiatric and behavioral conditions. Consequently, amygdala neurons may also represent potential targets for behavioral-change interventions that aim to improve individual decision-making. [ABSTRACT FROM AUTHOR]

Although physical exercise has obvious benefits in brain physiology, the molecular biomarkers induced by exercise protocols are inconclusive. Evidence indicates that exercise interventions are effective in shaping brain physiology. However, the potential mediator for improving brain functions is uncertain. CREB is one of the potential targets of exercise that triggers various molecular cross-talk to improve neurogenesis, long-term potentiation, and synaptogenesis. Therefore, CREB may be situated on the causal path between maintaining brain health and exercising. To support this, studies have shown that exercise-mediated CREB phosphorylation improves cognitive functions and memory. In addition, among the protocols of exercise (types, duration, and frequency), the intensity has been reported to be the most effective in triggering CREB-mediated molecular signaling. For example, HIT increases the synthesis of CREB, which may not only induce brain physiology but also induce brain pathology by higher activation of its downstream targets, such as BDNF. Therefore, this review aims to understand the effects of HIT on CREB function and how HIT can mediate the CREB-induced molecular cross-talk for maintaining brain health. [ABSTRACT FROM AUTHOR]

Neuromorphic circuits offer a means to emulate or interface with the nervous system, yet detailed model implementations remain underexplored. This paper proposes an analog CMOS realization of the Pinsky-Rinzel (PR) neuron model, a conductance-based two-compartmental model of hippocampal CA3 pyramidal neurons capable of producing spike and complex bursting. To achieve first-order dynamics, we introduce a seven-segment approximation circuit with a customizable architecture based on the variable's behavior. For second-order dynamics, we modify the architectures of the log-domain low pass filter and Tau-cell. To enhance power and area efficiency, we implement conductances and reversal potentials using current mirrors within circuit blocks. Additionally, we propose four compact subthreshold multipliers specifically tailored for neuromorphic systems, while eliminating any unnecessary DC current across circuit blocks. These modifications led to a 150-fold reduction in power consumption compared to state-of-the-art conductance-based implementations. Simulation results demonstrate the independent operation of soma and dendrite compartments for spike generation, while coupling generates complex bursting. Realized in TSMC 65 nm CMOS technology with a 0.2 V subthreshold power supply, the circuit operates in the 50–300 kHz frequency range, showcasing an average power consumption of 125.1 nW. Finally, Monte Carlo simulations for both spiking and complex bursting modes are evaluated in 200 points. These results not only validate the functionality of the proposed circuit but also position it as a versatile platform for implementing various conductance-based models, including astrocytes. [ABSTRACT FROM AUTHOR]

Copper (Cu) is an essential trace element involved in fundamental physiological processes in the human body. Even slight disturbances in the physiological Cu homeostasis are associated with the manifestation of neurodegenerative diseases. While suggesting a crucial role of Cu in the pathogenesis, the exact mechanisms of Cu neurotoxicity involved in the onset and progression of neurological diseases are far from understood. This study focuses on the molecular and cellular mechanisms of Cu-mediated neurotoxicity in human brain cells. First, the cytotoxic potential of Cu was studied in fully differentiated, human neurons (LUHMES cells). Lysosomal integrity was considerably affected following incubation with 420 µM CuSO4 for 48 h. Further mechanistic studies revealed mitochondria and neuronal network as most susceptible target organelles (already at 100 µM CuSO4, 48 h), while the generation of reactive oxygen species turned out to be a rather later consequence of Cu toxicity. Besides Cu, the homeostasis of other elements might be involved and are likely to contribute to the pathology of Cu-mediated neurological disorders. Besides Cu, also effects on the cellular levels of magnesium, calcium, iron, and manganese were observed in the neurons, presumably aggravating the consequences of Cu neurotoxicity. In conclusion, insights in the underlying mode of action will foster the development of treatment strategies against Cu-mediated neurological diseases. Particularly, the interplay of Cu with other elements might provide a powerful diagnostic tool and might be used as therapeutic approach. [ABSTRACT FROM AUTHOR]

Introduction Acute pain in cancer is an important but often overlooked feature of many patients' oncological journey. Cancer-related pain is associated commonly with more persistent pain states caused by both the disease and its treatment, but there are numerous causes of acute pain which can develop in patients with cancer. This pain is frequently severe, can be challenging to manage and its suboptimal control can directly impact on oncological outcomes. This narrative review provides an overview of several causes of acute pain in patients with cancer and management approaches. Methods A focused literature review was conducted to encompass the search terms 'acute pain', 'oncology' and 'cancer' in adult and paediatric populations. Results Acute pain is common in patients with cancer with a number of pain generators identified. Broadly, these are disease- and treatment-related but commonality in pain mechanisms and features are present. Importantly, these pain states do not occur in isolation; a patient may experience multiple acute pain episodes during their oncology journey. Discussion As the oncological treatment landscape shifts and increasing numbers of novel treatments are employed, the number of causes of acute pain in patients with cancer rises. This pain is often managed by non-pain specialists and suboptimal control has a variety of deleterious effects. It is important that awareness of acute pain in the oncological population is increased and treatment approaches, which adopt a biopsychosocial structure, are optimised. [ABSTRACT FROM AUTHOR]

The supramammillary nucleus (SuM), located in the caudal hypothalamus, includes wake-promoting glutamatergic neurones. Their potential role in regulating states of consciousness during general anaesthesia remains unknown. We used in vivo fibre photometry, c-Fos staining, chemogenetic and optogenetic manipulations, and electroencephalography/electromyography to explore the roles of glutamatergic SuM neurones (SuMVglut2 neurones) at different phases of sevoflurane anaesthesia. Rabies-mediated retrograde and anterograde tract tracing were used to investigate the monosynaptic glutamatergic inputs from the medial septum (MS) to SuM. Their roles in sevoflurane anaesthesia were investigated by in vivo fibre photometry and optogenetic manipulations. The population activity of SuMVglut2 neurones decreased at loss of consciousness but increased during recovery of consciousness under sevoflurane anaesthesia. Their activity also decreased during suppression but increased during bursts in sevoflurane-induced burst-suppression oscillations. Activating SuMVglut2 neurones chemogenetically or optogenetically decreased sensitivity to sevoflurane, induced behavioural arousal and cortical activation during continuous steady-state anaesthesia, and stable burst-suppression oscillations under sevoflurane. In contrast, chemogenetic or optogenetic inhibition of SuMVglut2 neurones increased sensitivity to sevoflurane or intensified cortical inhibition during sevoflurane anaesthesia. Retrograde and anterograde tracing verified monosynaptic projections from MSVglut2 neurones to SuMVglut2 neurones. The activity of MSVglut2 SuM terminals increased during loss of consciousness but recovered during recovery of consciousness. Optogenetic activation or inhibition of MSVglut2 SuM terminals induced cortical activation or inhibition, respectively, during sevoflurane anaesthesia. Activation of SuMVglut2 neurones or the glutamatergic septo-supramammillary circuit induces behavioural arousal and cortical activation during sevoflurane anaesthesia. [ABSTRACT FROM AUTHOR]

The cognitive dysfunction in the brain cause severe pathological consequences such as Alzheimer’s disease (AD), Parkinson’s disease. The current treatments are cost expensive and also cause negative side effects. Therefore it is inevitable to develop natural phyto-compounds as a drug like molecules to treat neurodegenerative diseases. In this context, we have assayed the neuroprotective effects of betanin, an indole derivative, in the neuroblastoma cell line SHSY-5Y cells. The neuroprotective effect was investigated in the β-amyloid (Aβ) - induced SHSY-5Y cells; betanin (25 µg) protected the SHSY-5Y cells from the toxic effects and maintained the cell viability. Moreover, the acridine orange and ethidum Bromide staining decipher that treatment of betanin in the Aβ-induced SHSY-5Y cells maintain the cell viablity sustainably. The Reactive Oxygen Species (ROS) assay infers that betanin quenches the generation of free radicals progressively in the Aβ-induced SHSY-5Y cells. In addition, the autophagy determination by flow cytometry revealed that betanin induces autophagy to remove the neurodegenerated cells. Further, we examined the docking and simulation patterns with the angiotensin-converting enzyme (ACE), TNF-α converting enzyme (TACE), glycogen synthase kinase 3 (GK3), and acetylcholinesterase enzymes (AChE) and amyloid precursor protein (APP). The insilico docking analysis denotes that betanin had a significant docking score with the target molecules. Thus, from the invitro and insilico studies, betanin strongly inhibit the toxic effects of Aβand protect the cells from degeneration. [ABSTRACT FROM AUTHOR]

Background: As a prevalent cerebrovascular disorder, cerebral infarction (CI) has garnered extensive attention globally due to its high incidence and substantial fatality rate. Ischemia-reperfusion injury (IRI) exacerbates not only neuronal demise but also amplifies neural functional impairment. Tanshinone IIA (Tan IIA) has been identified to confer protection against IRI, yet the precise underlying mechanisms remain elusive. This work aimed to delve into the mechanistic role of Tan IIA in CI, with the goal of furnishing more distinct theoretical substantiation for its clinical application. Methods: Initially, a middle cerebral artery embolization model group (MCAO) model was established, followed by the categorization of rats into distinct groups based on different administration modes. Therapeutic effects were evaluated through indices including mortality rate, cerebral tissue water content, CI proportion, and neural functional scoring. Meanwhile, cellular apoptosis rates in hippocampal and cortical tissues, as well as levels of oxidative stress molecules (OSM), Sirtuin 1 (SIRT1), Forkhead box O3 (FOXO3α), and inflammatory factors, were examined to explore the mechanism of action. Results: This work revealed that within varying doses of Tan IIA groups, as dosage escalated, mortality rate, cerebral edema severity, CI proportion, and neural functional scoring gradually diminished. Notably, the 35 mg/kg dose group exhibited the most significant reductions, with decreases of 74.9%, 12.7%, 47.5%, and 54%, respectively. Cellular apoptosis rates in hippocampal and cortical tissues displayed a stepwise descending trend, with the 35 mg/kg dose group showcasing the largest reduction. SIRT1 and FOXO3α proteins exhibited a steady increase, with the 35 mg/kg dose group manifesting respective elevations of 87.9% and 65.5%, the highest among all groups. Antioxidant molecules glutathione (GSH) and superoxide dismutase (SOD) contents progressively increased, whereas malondialdehyde (MDA) and nitric oxide (NO) content decreased. The 35 mg/kg dose group recorded the highest increments of 49.1% and 58.1% for GSH and SOD content, while achieving the greatest reductions of 55.6% and 56.2% for MDA and NO content. Expression of inflammatory factors, namely tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and interleukin-6 (IL-6), gradually declined, with reductions of 42.1%, 32.2%, and 29.1%, respectively, in the 35 mg/kg dose group, exhibiting drastic differences (p < 0.05). Conclusion: In conclusion, this research elucidates that Tan IIA improves cerebral edema and neural function by elevating intracellular expression of SIRT1 and FOXO3α proteins, modulating OSM and inflammatory factors. These findings yielded robust experimental support for the potential use of Tan IIA as a therapeutic agent for CI. [ABSTRACT FROM AUTHOR]

• Lipopolysaccharide (LPS)-induced neuroinflammation led to hippocampal neuron activation of in primary co-culture with glia. • LPS-induced hippocampal neuroinflammation disrupted goal-directed action and locomotor activity in mice of both sexes. • LPS-induced hippocampal neuroinflammation disrupted food seeking behaviours and memories in a sex-specific manner. • Chronic LPS-induced hippocampal neuroinflammation increased neuronal activation in female mice and decreased it in males. Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt this behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation. However, when the same endotoxin was applied to mixed neuronal/glial cultures it did increase neuronal activation, providing initial indications of how it might be able to effect behavioural change. We next showed neuroinflammatory effects on behaviour directly, demonstrating that intra-hippocampal administration of the same endotoxin increased locomotor activity and accelerated goal-directed learning in both male and female mice. In contrast, lipopolysaccharide-induced hippocampal neuroinflammation caused sex-specific disruptions to the acquisition of instrumental actions and to Pavlovian food-approach memories. Finally, we showed that LPS-induced hippocampal neuroinflammation had a sexually dimorphic effect on neuronal activation: increasing it in females and decreasing it in males. [ABSTRACT FROM AUTHOR]

The counting and characterization of neurons in primary cultures have long been areas of significant scientific interest due to their multifaceted applications, ranging from neuronal viability assessment to the study of neuronal development. Traditional methods, often relying on fluorescence or colorimetric staining and manual segmentation, are time consuming, labor intensive, and prone to error, raising the need for the development of automated and reliable methods. This paper delves into the evaluation of three pivotal deep learning techniques: semantic segmentation, which allows for pixel-level classification and is solely suited for characterization; object detection, which focuses on counting and locating neurons; and instance segmentation, which amalgamates the features of the other two but employing more intricate structures. The goal of this research is to discern what technique or combination of those techniques yields the optimal results for automatic counting and characterization of neurons in images of neuronal cultures. Following rigorous experimentation, we conclude that instance segmentation stands out, providing superior outcomes for both challenges. Identifying the optimal pathway for characterizing neurons in complex cultures through structured experimentation [ABSTRACT FROM AUTHOR]

Stromal interaction molecules (STIM)s are Ca2+ sensors in internal Ca2+ stores of the endoplasmic reticulum. They activate the store-operated Ca2+ channels, which are the main source of Ca2+ entry in non-excitable cells. Moreover, STIM proteins interact with other Ca2+ channel subunits and active transporters, making STIMs an important intermediate molecule in orchestrating a wide variety of Ca2+ influxes into excitable cells. Nevertheless, little is known about the role of STIM proteins in brain functioning. Being involved in many signaling pathways, STIMs replenish internal Ca2+ stores in neurons and mediate synaptic transmission and neuronal excitability. Ca2+ dyshomeostasis is a signature of many pathological conditions of the brain, including neurodegenerative diseases, injuries, stroke, and epilepsy. STIMs play a role in these disturbances not only by supporting abnormal store-operated Ca2+ entry but also by regulating Ca2+ influx through other channels. Here, we review the present knowledge of STIMs in neurons and their involvement in brain pathology. [ABSTRACT FROM AUTHOR]

Neuron models have attracted a lot of attention recently, both in mathematics and neuroscience. We are interested in studying long-time and large-population emerging properties in a simplified toy model. From a mathematical perspective, this amounts to studying the long-time behaviour of a degenerate reflected diffusion process. Using coupling arguments, the flow is proven to be a contraction of the Wasserstein distance for long times, which implies the exponential relaxation toward a (non-explicit) unique globally attractive equilibrium distribution. The result is extended to a McKean-Vlasov type non-linear variation of the model, when the mean-field interaction is sufficiently small. The ergodicity of the process results from a combination of deterministic contraction properties and local diffusion, the noise being sufficient to drive the system away from non-contractive domains. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that currently lacks effective treatment options. This study aimed to identify potential therapeutic targets for the treatment of AD using comprehensive bioinformatics methods and machine learning algorithms. By integrating differential gene expression analysis, weighted gene co-expression network analysis, Mfuzz clustering, single-cell RNA sequencing, and machine learning algorithms including LASSO regression, SVM-RFE, and random forest, five hub genes related to AD, including PLCB1, NDUFAB1, KRAS, ATP2A2, and CALM3 were identified. PLCB1, in particular, exhibited the highest diagnostic value in AD and showed significant correlation with Braak stages and neuronal expression. Furthermore, Noscapine, PX-316, and TAK-901 were selected as potential therapeutic drugs for AD based on PLCB1. This research provides a comprehensive and reliable method for the discovery of AD therapeutic targets and the construction of diagnostic models, offering important insights and directions for future AD treatment strategies and drug development. [ABSTRACT FROM AUTHOR]

Oxidative stress is recognized as a critical contributor to the advancement of neurological diseases, thereby rendering the alleviation of oxidative stress a pivotal strategy in the therapeutic management of such conditions. Sesamol, the principal constituent of sesame oil, has been the subject of extensive research due to its significant antioxidant properties, especially its ability to effectively counteract oxidative stress within the central nervous system and confer neuroprotection. While sesamol demonstrates potential in the treatment and prevention of neurological diseases, its modulation of oxidative stress is complex and not yet fully understood. This review delves into the neuroprotective effects arising from sesamol's antioxidant properties, analyzing how its antioxidative capabilities impact neurological diseases. It provides a theoretical foundation and unveils potential novel therapeutic applications of sesamol in the treatment of neurological disorders through the modulation of oxidative stress. [ABSTRACT FROM AUTHOR]

AbstractWe studied the protective effects of Pandanus tectorius fruits (PTF) on Schwann cells and sciatic nerve damage in diabetic peripheral neuropathy (DPN) rats. PTF improved RSC96 cell viability and increased Nrf2, Keap1, HO-1, and NQO1 expression. PTF reduced apoptosis and ROS in high glucose-treated cells, which was reversed by Nrf2 siRNA. Co-treatment with SFN further decreased apoptosis and ROS. PTF increased SOD, GSH-Px, NGF, IGF-1, and VEGF activities, reduced by Nrf2 knockdown but restored with SFN. MDA levels showed opposite trends. In DPN rats, PTF reduced pain and prevented nerve damage, suggesting it alleviates DPN by activating the Nrf2/Keap1 pathway. [ABSTRACT FROM AUTHOR]

Diabetes is a global epidemic, and its pathogenesis involves multiple factors. Diabetic peripheral neuropathy (DPN) is one of its clinical complications, which brings a serious burden to the lives of patients. Pandanus tectorius fruits (PTF) extract has attracted much attention due to its rich bioactive components and is considered to have potential effects in treating DPN. The present study aims to deeply explore the molecular mechanism of PTF extract in treating diabetic peripheral neuropathy, focusing on the regulatory effect of the Nrf2/Keap1 signalling pathway. The blood glucose changes and behavioural changes of DPN rats before and after PTF treatment were detected. Histological myelin staining was performed using Luxol fast blue (LFB) staining. TUNEL staining was used to observe the apoptosis of sciatic nerve cells. TEM observation of the ultrastructure of dorsal root ganglion. ELISA and kits detect NGF, IGF-1, VEGF, SOD, GSH-Px, and malondialdehyde (MDA). Western blot detects Nrf2, Keap1, HO-1 and NQO1. This experiment found that PTF extract has significant blood glucose control and analgesic effects on DPN rats. PTF extract can also inhibit the apoptosis of sciatic nerve cells in DPN rats and protect the structural integrity of myelin sheaths. The ultrastructure of dorsal root ganglia was improved after PTF treatment. The neuroactive factors (IGF-1, VEGF) in rats with DPN under a high-fat diet were significantly reduced, NGF was overexpression, the oxidative stress-related factors SOD and GSH-Px were reduced, and the levels of MDA were increased. After treatment with PTF, the positive drug a-lipoic acid reversed these abnormalities, enhanced levels of neuroactive factors, and mitigated oxidative stress. Western blot analysis showed that in DPN, the expression of Nrf2, HO-1 and NQO1 proteins in the sciatic nerve was down-regulated, Keap1 was overexpression, while PTF and a-lipoic acid treatment led to their upregulation. Adding the Nrf2 inhibitor Brusatol to the DPN + PTF group inhibited the up-regulating effect of PTF on these proteins. In summary, PTF extract can effectively reduce blood glucose and pain perception in DPN rats, promote antioxidant capacity, and protect the sciatic nerve through the Nrf2/Keap1 signalling pathway, thereby achieving the purpose of treating DPN. [ABSTRACT FROM AUTHOR]

Artificial neurons with bio-inspired firing patterns have the potential to significantly improve the performance of neural network computing. The most significant component of an artificial neuron circuit is a large amount of energy consumption. Recent literature has proposed memristors as a promising option for synaptic implementation. In contrast, implementing memristive circuitry through neuron hardware presents significant challenges and is a relevant research topic. This paper describes an efficient circuit-level mixed CMOS memristor artificial neuron network with a memristor synapse model. From this perspective, the paper describes the design of artificial neurons in standard CMOS technology with low power utilization. The neuron circuit response is a modified version of the Morris-Lecar theoretical model. The suggested circuit employs memristor-based artificial neurons with Dual Transistor and Dual Memristor (DTDM) synapse circuit. The proposed neuron network produces a high spiking frequency and low power consumption. According to our research, a memristor-based Morris Lecar (ML) neuron with a DTDM synapse circuit consumes 12.55 pW of power, the spiking frequency is 22.72 kHz, and 2.13 fJ of energy per spike. The simulations were carried out using the Spectre tool with 45 nm CMOS technology. [ABSTRACT FROM AUTHOR]

[Display omitted] • Intrathecal injection of 10 nmol NPFF potentiated morphine-induced analgesia. • Intrathecal injection of 10 pmol NPFF attenuated morphine-induced analgesia. • Both the pro- and anti-opioid effects of NPFF were mediated by NPFFR2. • Blockade of spinal NPFFR2 selectively regulated MOR agonists-induced analgesia. • NPFF exhibited anti-morphine effects in primary-cultured spinal neurons. Increasing evidence indicates that neuropeptide FF (NPFF) produces analgesic effects and augments opioid-induced analgesia at the spinal level. However, our recent research demonstrated that NPFF exerted complex opioid-modulating effects in an inflammatory pain model after intrathecal (i.t.) injection. Consistent with previous findings, we found that i.t. NPFF dose-dependently attenuated complete Freund's adjuvant-induced pain hypersensitivity. Interestingly, pharmacological results illustrated that NPFF exhibited opposite opioid-modulating effects at the spinal level depending on its administration dosage, wherein i.t. NPFF potentiated morphine-induced anti-allodynia at the dose of 10 nmol, while attenuated morphine analgesia at an ultra-low-dose of 10 pmol. Behavioral results obtained from neuropeptide FF receptor 2 (NPFFR2) knockout animals suggested that both pro- and anti-opioid effects of NPFF were mediated by NPFFR2. Moreover, these modulating effects of spinal NPFFR2 were selectively targeting mu-opioid receptor, had no effect on delta- and kappa-opioid receptor agonist-induced analgesia. Finally, the opioid-modulating effects of NPFF were further verified using in vitro calcium imaging assay, demonstrating that pretreated with NPFF in primary-cultured spinal neurons significantly attenuated the inhibitory effects of morphine on high-K+-induced neuronal excitability. Taken together, our results suggested that NPFF exhibited dual modulating effects on morphine-induced analgesia after i.t. administration, which provides a possible mechanism to explain the complex opioid-modulating effects of endogenous NPFF systems. [ABSTRACT FROM AUTHOR]

Introduction: The hippocampal formation exhibits complex and context-dependent activity patterns and dynamics, e.g., place cell activity during spatial navigation in rodents or remapping of place fields when the animal switches between contexts. Furthermore, rodents show context-dependent renewal of extinguished behavior. However, the link between context-dependent neural codes and context-dependent renewal is not fully understood. Methods: We use a deep neural network-based reinforcement learning agent to study the learning dynamics that occur during spatial learning and context switching in a simulated ABA extinction and renewal paradigm in a 3D virtual environment. Results: Despite its simplicity, the network exhibits a number of features typically found in the CA1 and CA3 regions of the hippocampus. A significant proportion of neurons in deeper layers of the network are tuned to a specific spatial position of the agent in the environment—similar to place cells in the hippocampus. These complex spatial representations and dynamics occur spontaneously in the hidden layer of a deep network during learning. These spatial representations exhibit global remapping when the agent is exposed to a new context. The spatial maps are restored when the agent returns to the previous context, accompanied by renewal of the conditioned behavior. Remapping is facilitated by memory replay of experiences during training. Discussion: Our results show that integrated codes that jointly represent spatial and task-relevant contextual variables are the mechanism underlying renewal in a simulated DQN agent. [ABSTRACT FROM AUTHOR]

Apical and basal dendrites of pyramidal neurons receive anatomically and functionally distinct inputs, implying compartment-level functional diversity during behavior. To test this, we imaged in vivo calcium signals from soma, apical dendrites, and basal dendrites in mouse hippocampal CA3 pyramidal neurons during head-fixed navigation. To capture compartment-specific population dynamics, we developed computational tools to automatically segment dendrites and extract accurate fluorescence traces from densely labeled neurons. We validated the method on sparsely labeled preparations and synthetic data, predicting an optimal labeling density for high experimental throughput and analytical accuracy. Our method detected rapid, local dendritic activity. Dendrites showed robust spatial tuning, similar to soma but with higher activity rates. Across days, apical dendrites remained more stable and outperformed in decoding of the animal's position. Thus, population-level apical and basal dendritic differences may reflect distinct compartment-specific input-output functions and computations in CA3. These tools will facilitate future studies mapping sub-cellular activity and their relation to behavior. The authors develop an analysis package for characterizing the activity of neural dendrites and soma using optical imaging and show that apical dendrites are more stable in spatial representations than basal dendrites in mouse hippocampal area CA3. [ABSTRACT FROM AUTHOR]

Amblyopia, a highly prevalent loss of visual acuity, is classically thought to result from cortical plasticity. The dorsal lateral geniculate nucleus (dLGN) has long been held to act as a passive relay for visual information, but recent findings suggest a largely underestimated functional plasticity in the dLGN. However, the cellular mechanisms supporting this plasticity have not yet been explored. We show here that monocular deprivation (MD), an experimental model of amblyopia, reduces the intrinsic excitability of dLGN cells. Furthermore, dLGN neurons exhibit long-term potentiation of their intrinsic excitability (LTP-IE) when suprathreshold afferent retinal inputs are stimulated at 40 hertz or when spikes are induced with current injection. LTP-IE is observed after eye opening, requires calcium influx, is expressed through the down-regulation of Kv1 channels, and is altered following MD. In conclusion, our study provides the first evidence for intrinsic plasticity in dLGN neurons induced by natural stimuli. [ABSTRACT FROM AUTHOR]

Reward prediction errors (RPEs) quantify the difference between expected and actual rewards, serving to refine future actions. Although reinforcement learning (RL) provides ample theoretical evidence suggesting that the long-term accumulation of these error signals improves learning efficiency, it remains unclear whether the brain uses similar mechanisms. To explore this, we constructed RL-based theoretical models and used multiregional two-photon calcium imaging in the mouse dorsal cortex. We identified a population of neurons whose activity was modulated by varying degrees of RPE accumulation. Consequently, RPE-encoding neurons were sequentially activated within each trial, forming a distributed assembly. RPE representations in mice aligned with theoretical predictions of RL, emerging during learning and being subject to manipulations of the reward function. Interareal comparisons revealed a region-specific code, with higher-order cortical regions exhibiting long-term encoding of RPE accumulation. These results present an additional layer of complexity in cortical RPE computation, potentially augmenting learning efficiency in animals. [ABSTRACT FROM AUTHOR]

Background: Understanding how enteric neural crest cells (ENCCs) differentiate into neurons is crucial for neurogenesis therapy and gastrointestinal disease research. This study explores how magnesium ions regulate the glycolytic pathway to enhance ENCCs differentiation into neurons. Materials and methods: We used polymerase chain reaction, western blot, immunofluorescence, and multielectrode array techniques to assess magnesium ions' impact on ENCCs differentiation. Non-targeted metabolomic sequencing, cellular acidification rate, oxygen consumption, and western blot analyzed sugar metabolism changes. D-glucose-13C6 isotope tracing identified key glucose flux changes. Surface plasmon resonance was used to detect the binding affinity of magnesium ions with key glycolysis genes. The elastic modulus of the hydrogel was measured using a universal testing machine, while pore size and porosity were assessed with scanning electron microscopy. Swelling ratios were determined using gravimetric analysis. In vivo, ENCCs in hydrogels were transplanted into renal capsule and subcutaneously, and magnesium ions' effects on ENCCs differentiation were evaluated. Results: Magnesium ions increased glycolysis levels during ENCCs differentiation into neurons, along with significant upregulation of neuronal markers β-Tubulin and ubiquitin C-terminal hydrolase L1, and enhanced functional neuronal properties. D-glucose-13C6 tracing results showed increased carbon flux in the glycolytic pathway after magnesium supplementation. The binding affinity of magnesium ions with the glycolytic key enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 was found to be 1.08 μM. Inhibiting glycolysis suppressed ENCCs differentiation into neurons, emphasizing its crucial role. The double-cross-linked hydrogel gelatin methacryloyl—alginate (gelMA—ALMA), cross-linked with magnesium ions, showed promise in enhancing ENCCs differentiation in vivo without causing systemic hypermagnesemia. Conclusion: Magnesium ions promote ENCCs differentiation into neurons by activating the Warburg effect. The GelMA-ALMA hydrogel serves as an effective localized magnesium delivery system, supporting neuronal differentiation in vivo. Magnesium ions target PFKFB3, enhancing glucose flux towards G3P and subsequent lactate production, while also promoting ENCCs differentiation into neurons by facilitating NAD+ generation, suppressing ROS, and maintaining mitochondrial homeostasis. Mg: Mg2+, Glu: glucose, LA: lactic acid. Ref to the creation software of the picture. [ABSTRACT FROM AUTHOR]

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which transmits circadian information to other brain regions and regulates the timing of sleep and wakefulness. Neurons in the lateral hypothalamus (LH), particularly those producing melanin-concentrating hormone (MCH) and orexin, are key regulators of sleep and wakefulness. Although the SCN receives nonphotic input from other brain regions, the mechanisms of functional input from the LH to the SCN remain poorly understood. Here, we show that orexin and MCH peptides influence the circadian period within the SCN of both sexes. When these neurons are ablated, the circadian behavioral rhythms are lengthened under constant darkness. Using anterograde and retrograde tracing, we found that orexin and MCH neurons project to the SCN. Furthermore, the application of these peptides to cultured SCN slices shortened circadian rhythms and reduced intracellular cAMP levels. Additionally, pharmacological reduction of intracellular cAMP levels similarly shortened the circadian period in SCN slices. These findings suggest that orexin and MCH peptides from the LH contribute to the modulation of the circadian period in the SCN. [ABSTRACT FROM AUTHOR]

Stress is a potent modulator of pain. Specifically, acute stress due to physical restraint induces stress-induced analgesia (SIA). However, where and how acute stress and pain pathways interface in the brain are poorly understood. Here, we describe how the dorsal lateral septum (dLS), a forebrain limbic nucleus, facilitates SIA through its downstream targets in the lateral hypothalamic area (LHA) of mice. Taking advantage of transsynaptic viral-genetic, optogenetic, and chemogenetic techniques, we show that the dLS→LHA circuitry is sufficient to drive analgesia and is required for SIA. Furthermore, our results reveal that the dLS→LHA pathway is opioid-dependent and modulates pain through the pro-nociceptive neurons in the rostral ventromedial medulla (RVM). Remarkably, we found that the inhibitory dLS neurons are recruited specifically when the mice struggle to escape under restraint and, in turn, inhibit excitatory LHA neurons. As a result, the RVM neurons downstream of LHA are disengaged, thus suppressing nociception. Together, we delineate a poly-synaptic pathway that can transform escape behavior in mice under restraint to acute stress into analgesia. [ABSTRACT FROM AUTHOR]