Neuronal Population Activity Research Articles

Development of the sleep-wake switch in rats during the P2-P21 early infancy period.

In early infancy, rats randomly alternate between the sleeping and waking states-from postnatal day 2-10 (P2-P10), sleep and wake bouts are both exponentially distributed with increasing means, while from P10-P21 sleep and wake bout means continue to increase, though there is a striking qualitative shift in the distribution of wake bouts from exponential to power law. The behavioral states of sleep and wakefulness correspond to the activity of sleep-active and wake-active neuronal brainstem populations, with reciprocal inhibition between the two ensuring that only one population is active at a time. The locus coeruleus (LC) forms a third component of this circuit that rises in prominence during the P10-P21 period, as experimental evidence shows that an as-of-yet undeciphered interaction of the LC with sleep-active and wake-active populations is responsible for the transformation of the wake bout distribution from exponential to power law. Interestingly, the LC undergoes remarkable physiological changes during the P10-P21 period-gap junctions within the LC are pruned and network-wide oscillatory synchrony declines and vanishes. In this work, we discuss a series of models of sleep-active, wake-active, and the LC populations, and we use these models to postulate the nature of the interaction between these three populations and how these interactions explain empirical observations of sleep and wake bout dynamics. We hypothesize a circuit in which there is reciprocal excitation between the LC and wake-active population with inhibition from the sleep-active population to the LC that suppresses the LC during sleep bouts. During the P2-P10 period, we argue that a noise-based switching mechanism between the sleep-active and wake-active populations provides a simple and natural way to account for exponential bout distributions, and that the locked oscillatory state of the LC prevents it from impacting bout distributions. From P10-P21, we use our models to postulate that, as the LC gradually shifts from a state of synchronized oscillations to a state of continuous firing, reciprocal excitation between the LC and the wake-active population is able to gradually transform the wake bout distribution from exponential to power law.

Frontiers in the Development of Chemogenetic Therapies for the Treatment of Epilepsy

In recent years, the development of an on-demand treatment for epilepsy has been promoted using chemogenetics, by which neural activity of a target neuronal population is manipulated by systemic drug delivery. This paper outlines the mechanism of chemogenetic manipulation of neural activity, describes recent studies that have confirmed the efficacy of this technique in macaque monkeys, and discusses future developments toward clinical application of this technique.

Blazed oblique plane microscopy reveals scale-invariant inference of brain-wide population activity

Due to the size and opacity of vertebrate brains, it has until now been impossible to simultaneously record neuronal activity at cellular resolution across the entire adult brain. As a result, scientists are forced to choose between cellular-resolution microscopy over limited fields-of-view or whole-brain imaging at coarse-grained resolution. Bridging the gap between these spatial scales of understanding remains a major challenge in neuroscience. Here, we introduce blazed oblique plane microscopy to perform brain-wide recording of neuronal activity at cellular resolution in an adult vertebrate. Contrary to common belief, we find that inferences of neuronal population activity are near-independent of spatial scale: a set of randomly sampled neurons has a comparable predictive power as the same number of coarse-grained macrovoxels. Our work thus links cellular resolution with brain-wide scope, challenges the prevailing view that macroscale methods are generally inferior to microscale techniques and underscores the value of multiscale approaches to studying brain-wide activity.

Ventral Tegmental Area Glutamatergic Neurons Facilitated Emergence From Isoflurane Anesthesia Involves Excitation of Lateral Septum GABA-ergic Neurons in Mice.

Ventral tegmental area (VTA) glutamatergic neurons promote wakefulness in the sleep-wake cycle; however, their roles and neural circuit mechanisms during isoflurane (ISO) anesthesia remain unclear. Fiber photometry and in vivo electrophysiology were used to observe the changes in neuronal or terminal activity during ISO anesthesia and arousal processes. Optogenetic and anesthesia behaviors were used to investigate the effects of VTA glutamatergic neurons and their projections to the lateral septum (LS) during ISO anesthesia and arousal. Anterograde and retrograde tracings were performed to identify the connections between VTA glutamatergic neurons and the LS. Population activity and firing rates of VTA glutamatergic neurons decreased during ISO anesthesia (ISO: 95% confidence interval [CI], 0.83-2.06 Spikes.s -1 vs wake: 95% CI, 3.53-7.83 Spikes.s -1 ; P =.0001; n = 34 from 4 mice). Optogenetic activation of VTA glutamatergic neurons reduced the burst-suppression ratio in electroencephalography (laser: 95% CI, 13.09%-28.76% vs pre: 95% CI, 52.85%-71.59%; P =.0009; n = 6) and facilitated emergence (ChR2: 95% CI, 343.3-388.0 seconds vs mCherry: 95% CI, 447.6-509.8 seconds; P < .0001; n = 11/12) from ISO anesthesia. VTA glutamatergic neurons monosynaptically innervated LS γ-aminobutyric acid (GABA)-ergic neurons. The activity of VTA glutamatergic terminals in the LS decreased during ISO anesthesia, and optogenetic activation of the VTA glutamatergic terminals in the LS facilitated emergence from ISO anesthesia. Furthermore, optogenetic activation of VTA glutamatergic terminals increased the firing rates of LS γ-aminobutyric acid-ergic (GABAergic) neurons (laser: 95% CI, 0.85-4.03 Spikes.s -1 vs pre: 95% CI, 0.24-0.78 Spikes.s -1 ; P =.008; n = 23 from 4 mice) during ISO anesthesia. VTA glutamatergic neurons facilitated emergence from ISO anesthesia involving excitation of LS GABAergic neurons.

Neural mechanisms for spatial cognition across vertebrates

The ability to navigate the world is a critical cognitive skill that most animals use to find food, shelter, and mates. Understanding the neural basis of navigation requires probing how the brain encodes spatial information through the study of the activity of single neurons and neuronal populations. Classically in vertebrates, studies have centered on the rodent hippocampal formation, which led to the discovery of place, grid, head direction and other cell types. However, since navigation skills are essential to almost all vertebrates, spatial cognition in different species also needs to be explored. In recent years, as a result of advances in technology, new data have emerged on the ways in which space is represented during navigation in the brains of vertebrates other than rodents, including teleost fish, birds, and other mammal species. Here, we review the state of the art on the neural representation of an animal’s position and motion across vertebrates at the level of single neurons. We argue that it is time to pool information across vertebrates to identify the underlying algorithms that lead to successful navigation. Although rodent-based data are important, findings in rodents are unlikely to cover the full spectrum of neural computations supporting navigation strategies in the vertebrate kingdom. Studying other species can shed light on length scales such as in large environments, and different scenarios such as naturalistic environments that are hard to carry out in rodents. In addition, a rodent-centric view may neglect the fact that different species are likely to represent positions in the world in ways that do not exist in mammals. Finally, we provide an outlook for the future which includes prediction about findings in unexplored species, and the opportunities for discoveries and understanding in this field.

Neuronal Population Activity in Macaque Visual Cortices Dynamically Changes through Repeated Fixations in Active Free Viewing.

During free viewing, we move our eyes and fixate on objects to recognize the visual scene of our surroundings. To investigate the neural representation of objects in this process, we studied individual and population neuronal activity in three different visual regions of the brains of macaque monkeys (Macaca fuscata): the primary and secondary visual cortices (V1, V2) and the inferotemporal cortex (IT). We designed a task where the animal freely selected objects in a stimulus image to fixate on while we examined the relationship between spiking activity, the order of fixations, and the fixated objects. We found that activity changed across repeated fixations on the same object in all three recorded areas, with observed reductions in firing rates. Furthermore, the responses of individual neurons became sparser and more selective with individual objects. The population activity for individual objects also became distinct. These results suggest that visual neurons respond dynamically to repeated input stimuli through a smaller number of spikes, thereby allowing for discrimination between individual objects with smaller energy.

OR09-02 Chemogenetic Manipulation Of Brainstem Noradrenergic Neurons Modulates The Activity Of The Kisspeptin GnRH Pulse Generator In Mice

Abstract Disclosure: S. Vas: None. M. Ruiz-Cruz: None. S. Han: None. S. Hwa-Yeo: None. A.E. Herbison: None. The kisspeptin neurons in the arcuate nucleus (ARNKISS) represent the GnRH pulse generator that drives pulsatile luteinizing hormone secretion. These neurons serve as a hub to integrate multiple cues, such as the negative feedback control from steroid hormones, as well as metabolic, and stress-related inputs. Brainstem noradrenergic (NA) neurons have long been implicated in the control of GnRH pulse generator frequency and fertility but the precise mechanisms through which they operate, and their roles remain unclear. Here we used intersectional Cre-lox and FLP-FRT recombination approaches to couple ARNKISS neuron GCaMP6 fiber photometry with the brainstem NA DREADD (Designer Receptor Exclusively Activated by Designer Drug) modulation to investigate the role that NA may play in controlling ARNKISS pulse generator activity. Kiss1-Cre,GCaMP6s mice were crossed with a mouse line in which FLP recombinase is expressed selectively in dopamine β-hydroxylase (NA) neurons. Adult female mice were injected bilaterally with a FLP-dependent retrograde viral vector (AAVrg-hSyn-fDIO-hM3D(Gq)-mCherry-WPREpA) into the mid-caudal ARN to express excitatory (hM3Dq) DREADD receptors selectively in brainstem NA neurons that project to the ARN. An optical fiber was then implanted to detect the calcium-dependent population activity of KISSARN neurons. Histology revealed m-Cherry/DREADD expression in small sub-populations of tyrosine-hydroxylase neurons located in the brainstem A1, A2 and A6, confirming direct innervation from these regions to the ARN. Selective activation of these NA neurons with 1.5 and 3 mg/kg CNO (s.c.) in diestrous-stage mice, dose-dependently inhibited the frequency of the pulse generator synchronization episodes by 48-76% over 4 hours. These observations demonstrate that, when activated, brainstem NA neurons exert an inhibitory influence on the kisspeptin GnRH pulse generator in intact female mice. The new data may help to dissect how key components of the stress-responsive circuitry impact the central regulation of fertility. Presentation: Friday, June 16, 2023

Chronic Pallidal Local Field Potentials Are Associated With Dystonic Symptoms in Children

BackgroundNovel deep brain stimulation devices can record local field potentials (LFPs), which represent the synchronous synaptic activity of neuronal populations. The clinical relevance of LFPs in patients with dystonia remains unclear. ObjectivesWe sought to determine whether chronic LFPs recorded from the globus pallidus internus (GPi) were associated with symptoms of dystonia in children. Materials and MethodsTen patients with heterogeneous forms of dystonia (genetic and acquired) were implanted with neurostimulators that recorded LFP spectral snapshots. Spectra were compared across parent-reported asymptomatic and symptomatic periods, with daily narrowband data superimposed in 24 one-hour bins. ResultsSpectral power increased during periods of registered dystonic symptoms: mean increase = 102%, CI: (76.7, 132). Circadian rhythms within the LFP narrowband time series correlated with dystonic symptoms: for delta/theta-waves, correlation = 0.33, CI: (0.18, 0.47) and for alpha waves, correlation = 0.27, CI: (0.14, 0.40). ConclusionsLFP spectra recorded in the GPi indicate a circadian pattern and are associated with the manifestation of dystonic symptoms.

Development of multi-depth probing 3D microelectrode array to record electrophysiological activity within neural cultures

Microelectrode arrays (MEAs) play a crucial role in investigating the electrophysiological activities of neuronal populations. Although two-dimensional neuronal cell cultures have predominated in neurophysiology in monitoring in-vitro the electrophysiological activity, recent research shifted toward culture using three-dimensional (3D) neuronal network structures for developing more sophisticated and realistic neuronal models. Nevertheless, many challenges remain in the electrophysiological analysis of 3D neuron cultures, among them the development of robust platforms for investigating the electrophysiological signal at multiple depths of the 3D neurons’ networks. While various 3D MEAs have been developed to probe specific depths within the layered nervous system, the fabrication of microelectrodes with different heights, capable of probing neural activity from the surface as well as from the different layers within the neural construct, remains challenging. This study presents a novel 3D MEA with microelectrodes of different heights, realized through a multi-stage mold-assisted electrodeposition process. Our pioneering platform allows meticulous control over the height of individual microelectrodes as well as the array topology, paving the way for the fabrication of 3D MEAs consisting of electrodes with multiple heights that could be tailored for specific applications and experiments. The device performance was characterized by measuring electrochemical impedance, and noise, and capturing spontaneous electrophysiological activity from neurospheroids derived from human induced pluripotent stem cells. These evaluations unequivocally validated the significant potential of our innovative multi-height 3D MEA as an avant-garde platform for in vitro 3D neuronal studies.

Prostaglandin E2 Induces Long-Lasting Inhibition of Noradrenergic Neurons in the Locus Coeruleus and Moderates the Behavioral Response to Stressors.

Neuronal activity is modulated not only by inputs from other neurons but also by various factors, such as bioactive substances. Noradrenergic (NA) neurons in the locus coeruleus (LC-NA neurons) are involved in diverse physiological functions, including sleep/wakefulness and stress responses. Previous studies have identified various substances and receptors that modulate LC-NA neuronal activity through techniques including electrophysiology, calcium imaging, and single-cell RNA sequencing. However, many substances with unknown physiological significance have been overlooked. Here, we established an efficient screening method for identifying substances that modulate LC-NA neuronal activity through intracellular calcium ([Ca2+]i) imaging using brain slices. Using both sexes of mice, we screened 53 bioactive substances, and identified five novel substances: gastrin-releasing peptide, neuromedin U, and angiotensin II, which increase [Ca2+]i, and pancreatic polypeptide and prostaglandin D2, which decrease [Ca2+]i Among them, neuromedin U induced the greatest response in female mice. In terms of the duration of [Ca2+]i change, we focused on prostaglandin E2 (PGE2), since it induces a long-lasting decrease in [Ca2+]i via the EP3 receptor. Conditional knock-out of the receptor in LC-NA neurons resulted in increased depression-like behavior, prolonged wakefulness in the dark period, and increased [Ca2+]i after stress exposure. Our results demonstrate the effectiveness of our screening method for identifying substances that modulate a specific neuronal population in an unbiased manner and suggest that stress-induced prostaglandin E2 can suppress LC-NA neuronal activity to moderate the behavioral response to stressors. Our screening method will contribute to uncovering previously unknown physiological functions of uncharacterized bioactive substances in specific neuronal populations.SIGNIFICANCE STATEMENT Bioactive substances modulate the activity of specific neuronal populations. However, since only a limited number of substances with predicted effects have been investigated, many substances that may modulate neuronal activity have gone unrecognized. Here, we established an unbiased method for identifying modulatory substances by measuring the intracellular calcium signal, which reflects neuronal activity. We examined noradrenergic (NA) neurons in the locus coeruleus (LC-NA neurons), which are involved in diverse physiological functions. We identified five novel substances that modulate LC-NA neuronal activity. We also found that stress-induced prostaglandin E2 (PGE2) may suppress LC-NA neuronal activity and influence behavioral outcomes. Our screening method will help uncover previously overlooked functions of bioactive substances and provide insight into unrecognized roles of specific neuronal populations.

CA3 principal cell activation triggers hypersynchronous-onset seizures in a mouse model of mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy and it is characterized by seizures that are often refractory to medications. Seizures in MTLE have two main patterns of onset that have been termed hypersynchronous (HYP) and low-voltage fast (LVF) and are believed to mainly depend on the activity of excitatory principal cells and inhibitory interneurons, respectively. In this study, we investigated whether unilateral open-loop optogenetic activation of CaMKII-positive principal cells in the hippocampus CA3 region favors the generation of spontaneous HYP seizures in kainic acid-treated (KA) CaMKII-ChR2 mice. Optogenetic activation of CA3 principal cells (1 Hz, 180 s ON, 220 s OFF) was implemented for 15 days after KA-induced status epilepticus. We found that both LVF and HYP seizures occurred in nonstimulated CaMKII-ChR2 (n = 6) and stimulated CaMKII-Cre (n = 5) mice. In contrast, optogenetic activation of principal cells in CaMKII-ChR2 mice (n = 5) triggered only HYP seizures that were characterized by high fast ripple (250-500 Hz) rates during the pre-ictal and ictal periods. These results provide firm evidence that in MTLE spontaneous seizures with different onset patterns depend on distinct neuronal network mechanisms of generation. They also demonstrate that HYP seizures occurring in vivo along with their associated fast ripples depend on the activity of principal cells in the CA3 region.NEW & NOTEWORTHY Previous evidence suggested that different seizure onset patterns rely on the activity of distinct neuronal populations. In this study, we show for the first time that in vivo optogenetic stimulation of CaMKII principal cells in kainic acid-treated mice triggers hypersynchronous-onset seizures that are associated with fast ripples. Our findings indicate that in patients with predominant HYP-onset seizures, anticonvulsant treatments should be aimed at limiting the firing of principal neurons in the seizure onset zone.

Quantification of prefrontal cortical neuronal ensembles following conditioned fear learning in a Fos-LacZ transgenic rat with photoacoustic imaging in Vivo

Understanding the neurobiology of complex behaviors requires measurement of activity in the discrete population of active neurons, neuronal ensembles, which control the behavior. Conventional neuroimaging techniques ineffectively measure neuronal ensemble activity in the brain in vivo because they assess the average regional neuronal activity instead of the specific activity of the neuronal ensemble that mediates the behavior. Our functional molecular photoacoustic tomography (FM-PAT) system allows direct imaging of Fos-dependent neuronal ensemble activation in Fos-LacZ transgenic rats in vivo. We tested four experimental conditions and found increased FM-PAT signal in prefrontal cortical areas in rats undergoing conditioned fear or novel context exposure. A parallel immunofluorescence ex vivo study of Fos expression found similar findings. These findings demonstrate the ability of FM-PAT to measure Fos-expressing neuronal ensembles directly in vivo and support a mechanistic role for the prefrontal cortex in higher-order processing of response to specific stimuli or environmental cues.

High-speed multiplane confocal microscopy for voltage imaging in densely labeled neuronal populations.

Genetically encoded voltage indicators (GEVIs) hold immense potential for monitoring neuronal population activity. To date, best-in-class GEVIs rely on one-photon excitation. However, GEVI imaging of dense neuronal populations remains difficult because out-of-focus background fluorescence produces low contrast and excess noise when paired with conventional one-photon widefield imaging methods. To address this challenge, we developed an imaging system capable of efficient, high-contrast GEVI imaging at near-kHz rates and demonstrate it for in vivo and ex vivo imaging applications in the mouse neocortex. Our approach uses simultaneous multiplane imaging to monitor activity within contiguous tissue volumes with no penalty in speed or requirement for high excitation power. This approach, multi-Z imaging with confocal detection (MuZIC), permits high signal-to-noise ratio voltage imaging in densely labeled neuronal populations and is compatible with imaging through micro-optics. Moreover, it minimizes artifacts associated with concurrent imaging and optogenetic photostimulation for all-optical electrophysiology.

A dietary polyphenol metabolite alters CA1 excitability ex vivo and mildly affects cortico-hippocampal field potential generators in anesthetized animals.

Dietary polyphenols have beneficial effects in situations of impaired cognition in acute models of neurodegeneration. The possibility that they may have a direct effect on the electrical activity of neuronal populations has not been tested. We explored the electrophysiological action of protocatechuic acid (PCA) on CA1 pyramidal cells ex vivo and network activity in anesthetized female rats using pathway-specific field potential (FP) generators obtained from laminar FPs in cortex and hippocampus. Whole-cell recordings from CA1 pyramidal cells revealed increased synaptic potentials, particularly in response to basal dendritic excitation, while the associated evoked firing was significantly reduced. This counterintuitive result was attributed to a marked increase of the rheobase and voltage threshold, indicating a decreased ability to generate spikes in response to depolarizing current. Systemic administration of PCA only slightly altered the ongoing activity of some FP generators, although it produced a striking disengagement of infraslow activities between the cortex and hippocampus on a scale of minutes. To our knowledge, this is the first report showing the direct action of a dietary polyphenol on electrical activity, performing neuromodulatory roles at both the cellular and network levels.

Cortico-cortical paired associative stimulation conditioning superficial ventral premotor cortex-primary motor cortex connectivity influences motor cortical activity during precision grip.

The ventral premotor cortex (PMv) and primary motor cortex (M1) represent critical nodes of a parietofrontal network involved in grasping actions, such as power and precision grip. Here, we investigated how the functional PMv-M1 connectivity drives the dissociation between these two actions. We applied a PMv-M1 cortico-cortical paired associative stimulation (cc-PAS) protocol, stimulating M1 in both postero-anterior (PA) and antero-posterior (AP) directions, in order to induce long-term changes in the activity of different neuronal populations within M1. We evaluated the motor-evoked potential (MEP) amplitude, MEP latency and cortical silent period, in both PA and AP, during the isometric execution of precision and power grip, before and after the PMv-M1 cc-PAS. The repeated activation of the PMv-M1 cortico-cortical network with PA orientation over M1 did not change MEP amplitude or cortical silent period duration during both actions. In contrast, the PMv-M1 cc-PAS stimulation of M1 with an AP direction led to a specific modulation of precision grip motor drive. In particular, MEPs tested with AP stimulation showed a selective increase of corticospinal excitability during precision grip. These findings suggest that the more superficial M1 neuronal populations recruited by the PMv input are involved preferentially in the execution of precision grip actions. KEY POINTS: Ventral premotor cortex (PMv)-primary motor cortex (M1) cortico-cortical paired associative stimulation (cc-PAS) with different coil orientation targets dissociable neural populations. PMv-M1 cc-PAS with M1 antero-posterior coil orientation specifically modulates corticospinal excitability during precision grip. Superficial M1 populations are involved preferentially in the execution of precision grip. A plasticity induction protocol targeting the specific PMv-M1subpopulation might have important translational value for the rehabilitation of hand function.

Developmental emergence of cortical neurogliaform cell diversity.

GABAergic interneurons are key regulators of cortical circuit function. Among the dozens of reported transcriptionally distinct subtypes of cortical interneurons, neurogliaform cells (NGC) are unique: recruited by long-range excitatory inputs, source of slow cortical inhibition and able to modulate the activity of large neuronal populations. Despite their functional relevance, the developmental emergence and diversity of NGCs remains unclear. Here, by combining single-cell transcriptomics, genetic fate-mapping, electrophysiological and morphological characterization, we reveal that discrete molecular subtypes of NGCs, with distinctive anatomical and molecular profiles populate the neocortex. Furthermore, we show that NGC subtypes emerge gradually through development, as incipient discriminant molecular signatures are apparent in Preoptic Area (POA) born NGC precursors. By identifying NGC developmentally-conserved transcriptional programs, we report that the transcription factor Tox2 constitutes an identity hallmark across NGC subtypes. Using CRISPR-Cas9-mediated genetic loss-of-function, we show that Tox2 is critical for NGC development: POA-born cells lacking Tox2 fail to differentiate into NGCs. Together, these results reveal that NGCs are born from a spatially restricted pool of Tox2+ POA precursors, after which intra-type diverging molecular programs are gradually acquired post-mitotically and result in functionally and molecularly discrete NGC cortical subtypes.

Congenital blindness does not protect against a schizophrenia-related phenotype in rodents.

In 1950, Drs. Chevigny and Braverman authored a book about people's attitudes and prejudices toward the blind, noting that out of the thousands of schizophrenia patients they and others had treated, not one was blind. This led some to the intriguing hypothesis that congenital blindness may provide protection against schizophrenia. In this study, we directly examined whether congenital blindness protects against a schizophrenia-related phenotype in the methylazoxymethanol acetate (MAM) rodent model. Enucleation surgeries were performed on pups of MAM- or saline-treated rats on post-natal day 10. Once pups reached adulthood, male and female rats were evaluated for schizophrenia-like phenotypes using behavioral and electrophysiological measures. Consistent with previous work, MAM-treated rats display elevated dopamine neuron population activity, deficits in pre-pulse inhibition of startle, and hypersensitivity to psychomotor stimulants. Blindness did not protect against any of the MAM-induced phenotypes. Surprisingly, blindness in saline-treated rats caused changes in behavior and dopamine neuron activity. To examine the circadian rhythms of enucleated rats, we performed non-invasive measurements of corticosterone, a steroid hormone known to vary across the light/dark period, revealing blind rats display aberrant (non-cycling) corticosterone levels. Alterations in dopamine neuron activity and associated behaviors observed in blind rats are likely secondary to aberrant circadian regulation. This is the first preclinical study examining whether congenital blindness protects against a schizophrenia-like phenotype. While support of this hypothesis would have led to novel avenues of research and potential novel therapies, the results of current study suggest that blindness does not protect against schizophrenia.

Transformer-based light-evoked retinal spiking activity prediction.

Retinal visual prosthetic devices aim to restore vision via electrical stimulation delivered on the retina. While a number of devices have been commercially available, the stimulation strategies applied have not met the expectations of end-users. These stimulation strategies involve the neurons being activated based on their spatial properties, regardless of their functions, which may lead to lower visual acuity. The ability to predict light-evoked neural activities thus becomes crucial for the development of a retinal prosthetic device with better visual acuity. In addition to temporal nonlinearity, the spatial relationship between the 2-dimensional light stimulus and the spiking activity of neuron populations is the main barrier to accurate predictions. Recent advances in deep learning offer a possible alternative for neural activity prediction tasks. With proven performance on nonlinear sequential data in fields such as natural language processing and computer vision, the emerging transformer model may be adapted to predict neural activities. In this study, we built and evaluated a deep learning model based on the transformer to explore its predictive capacity in light-evoked retinal spikes. Our preliminary results show that the model is possible to achieve good performance in this task. The high versatility of deep learning models may allow us to make retinal activity predictions in more complex physiological environments and potentially enhance the visual acuity of retinal prosthetic devices in the future by enabling us to anticipate the desired neural responses to electrical stimuli.

α5-GABAA Receptor Modulation Reverses Behavioral and Neurophysiological Correlates of Psychosis in Rats with Ventral Hippocampal Alzheimer's Disease-like Pathology.

Of the 35 million people in the world suffering from Alzheimer's Disease (AD), up to half experience comorbid psychosis. Antipsychotics, used to treat psychosis, are contraindicated in elderly patients because they increase the risk of premature death. Reports indicate that the hippocampus is hyperactive in patients with psychosis and those with AD. Preclinical studies have demonstrated that the ventral hippocampus (vHipp) can regulate dopamine system function, which is thought to underlie symptoms of psychosis. A viral-mediated approach was used to express mutated human genes known to contribute to AD pathology: the Swedish (K670N, M671L), Florida (I716V), and London (V717I) mutations of amyloid precursor protein and two mutations (M146L and L286V) of presenilin 1 specifically in the vHipp, to investigate the selective contribution of AD-like pathology in this region. We observed a significant increase in dopamine neuron population activity and behavioral deficits in this AD-AAV model that mimics observations in rodent models with psychosis-like symptomatologies. Further, systemic administration of MP-III-022 (α5-GABAA receptor selective positive allosteric modulator) was able to reverse aberrant dopamine system function in AD-AAV rats. This study provides evidence for the development of drugs that target α5-GABAA receptors for patients with AD and comorbid psychosis.

Identification of Two FitzHugh-Nagumo Neuron Models Based on the Speed-Gradient and Filtering

The paper is devoted to the problem of parameter identification of two FitzHugh-Nagumo neuron models. The FitzHugh-Nagumo model is a simplification of the Hodgkin-Huxley model and it is very valuable for using on practice thanks to its simplicity. However, within an experiment only one variable of the FitzHugh-Nagumo model, the membrane potential, is measured, while another variable of cumulative effects of all slow ion currents responsible for restoring the resting potential of the membranes and both variables’ derivatives cannot be measured. This circumstance brings additional difficulties to the parameters estimation problem and, therefore, this case needs special attention. Firstly, the model was transformed to more simple form without unmeasured variables. Variables obtained from applying second-order real filter-differentiator were used instead of unmeasured derivatives in model’s equations. As a result, a linear equation was gotten and for this equation the identification goal, which guarantees correct parameters’ adjustment, was formulated and an adaptive system, parameters of which are estimations of original system’s parameters and an output of which estimates the output of the linear equation, was constructed. Then, the integral objective function was defined and the algorithm for the original model parameters identification was designed with the speed-gradient method. The results of computer simulation in the Simulink environment are presented. These results demonstrate that estimates of the model’s state and parameters converge to their true values rather fast. Unlike existing solutions of the FitzHugh-Nagumo identification problem, we propose a much easier deterministic algorithm. Moreover, the parameters are estimated for a system collected from two FitzHugh-Nagumo models, which opens perspectives for using the proposed method in modeling neuron population activity.