Aberrant Hippocampal Neuroregenerative Plasticity in Schizophrenia: Reactive Neuroblastosis as a Possible Pathocellular Mechanism of Hallucination.

Hallucination is a sensory perception that occurs in the absence of external stimuli during abnormal neurological disturbances and various mental diseases. Hallucination is recognized as a core psychotic symptom and is particularly more prevalent in individuals with schizophrenia. Strikingly, a significant number of subjects with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other neurological diseases like cerebral stroke and epileptic seizure also experience hallucination. While aberrant neurotransmission has been linked to the neuropathogenic events of schizophrenia, the precise cellular mechanism accounting for hallucinations remains obscure. Neurogenesis is a cellular process of producing new neurons from the neural stem cells (NSC)-derived neuroblasts in the brain that contribute to the regulation of pattern separation, mood, olfaction, learning, and memory in adulthood. Impaired neurogenesis in the hippocampus of the adult brain has been linked to stress, anxiety, depression, and dementia. Notably, many neurodegenerative disorders are characterized by the mitotic and functional activation of neuroblasts and cell cycle re-entry of mature neurons leading to a drastic alteration in neurogenic process, known as reactive neuroblastosis. Considering their neurophysiological properties, the abnormal integration of neuroblasts into the existing neural network or withdrawal of their connections can lead to abnormal synaptogenesis, and neurotransmission. Eventually, this would be expected to result in altered perception accounting for hallucination. Thus, this article emphasizes a hypothesis that aberrant neurogenic processes at the level of reactive neuroblastosis could be an underlying mechanism of hallucination in schizophrenia and other neurological diseases.

CPEB2-activated axonal translation of VGLUT2 mRNA promotes glutamatergic transmission and presynaptic plasticity.

BACKGROUND: Local translation at synapses is important for rapidly remodeling the synaptic proteome to sustain long-term plasticity and memory. While the regulatory mechanisms underlying memory-associated local translation have been widely elucidated in the postsynaptic/dendritic region, there is no direct evidence for which RNA-binding protein (RBP) in axons controls target-specific mRNA translation to promote long-term potentiation (LTP) and memory. We previously reported that translation controlled by cytoplasmic polyadenylation element binding protein 2 (CPEB2) is important for postsynaptic plasticity and memory. Here, we investigated whether CPEB2 regulates axonal translation to support presynaptic plasticity. METHODS: Behavioral and electrophysiological assessments were conducted in mice with pan neuron/glia- or glutamatergic neuron-specific knockout of CPEB2. Hippocampal Schaffer collateral (SC)-CA1 and temporoammonic (TA)-CA1 pathways were electro-recorded to monitor synaptic transmission and LTP evoked by 4 trains of high-frequency stimulation. RNA immunoprecipitation, coupled with bioinformatics analysis, were used to unveil CPEB2-binding axonal RNA candidates associated with learning, which were further validated by Western blotting and luciferase reporter assays. Adeno-associated viruses expressing Cre recombinase were stereotaxically delivered to the pre- or post-synaptic region of the TA circuit to ablate Cpeb2 for further electrophysiological investigation. Biochemically isolated synaptosomes and axotomized neurons cultured on a microfluidic platform were applied to measure axonal protein synthesis and FM4-64FX-loaded synaptic vesicles. RESULTS: Electrophysiological analysis of hippocampal CA1 neurons detected abnormal excitability and vesicle release probability in CPEB2-depleted SC and TA afferents, so we cross-compared the CPEB2-immunoprecipitated transcriptome with a learning-induced axonal translatome in the adult cortex to identify axonal targets possibly regulated by CPEB2. We validated that Slc17a6, encoding vesicular glutamate transporter 2 (VGLUT2), is translationally upregulated by CPEB2. Conditional knockout of CPEB2 in VGLUT2-expressing glutamatergic neurons impaired consolidation of hippocampus-dependent memory in mice. Presynaptic-specific ablation of Cpeb2 in VGLUT2-dominated TA afferents was sufficient to attenuate protein synthesis-dependent LTP. Moreover, blocking activity-induced axonal Slc17a6 translation by CPEB2 deficiency or cycloheximide diminished the releasable pool of VGLUT2-containing synaptic vesicles. CONCLUSIONS: We identified 272 CPEB2-binding transcripts with altered axonal translation post-learning and established a causal link between CPEB2-driven axonal synthesis of VGLUT2 and presynaptic translation-dependent LTP. These findings extend our understanding of memory-related translational control mechanisms in the presynaptic compartment.

Synaptic reorganization of synchronized neuronal networks with synaptic weight and structural plasticity.

Abnormally strong neural synchronization may impair brain function, as observed in several brain disorders. We computationally study how neuronal dynamics, synaptic weights, and network structure co-emerge, in particular, during (de)synchronization processes and how they are affected by external perturbation. To investigate the impact of different types of plasticity mechanisms, we combine a network of excitatory integrate-and-fire neurons with different synaptic weight and/or structural plasticity mechanisms: (i) only spike-timing-dependent plasticity (STDP), (ii) only homeostatic structural plasticity (hSP), i.e., without weight-dependent pruning and without STDP, (iii) a combination of STDP and hSP, i.e., without weight-dependent pruning, and (iv) a combination of STDP and structural plasticity (SP) that includes hSP and weight-dependent pruning. To accommodate the diverse time scales of neuronal firing, STDP, and SP, we introduce a simple stochastic SP model, enabling detailed numerical analyses. With tools from network theory, we reveal that structural reorganization may remarkably enhance the network's level of synchrony. When weaker contacts are preferentially eliminated by weight-dependent pruning, synchrony is achieved with significantly sparser connections than in randomly structured networks in the STDP-only model. In particular, the strengthening of contacts from neurons with higher natural firing rates to those with lower rates and the weakening of contacts in the opposite direction, followed by selective removal of weak contacts, allows for strong synchrony with fewer connections. This activity-led network reorganization results in the emergence of degree-frequency, degree-degree correlations, and a mixture of degree assortativity. We compare the stimulation-induced desynchronization of synchronized states in the STDP-only model (i) with the desynchronization of models (iii) and (iv). The latter require stimuli of significantly higher intensity to achieve long-term desynchronization. These findings may inform future pre-clinical and clinical studies with invasive or non-invasive stimulus modalities aiming at inducing long-lasting relief of symptoms, e.g., in Parkinson's disease.

Want to learn? think again!

One of the best ways to improve new learning and increase memory strength is by reprocessing the recently acquired information, for example, by thinking of it again. Synaptic plasticity, the process by which neurons change the strength of their connections with each other, is fundamental for learning and memory formation. Yet, at present, it is unclear how reprocessing information drives synaptic plasticity to support memory improvement. A new study suggests that reprocessing enhances memory formation by recruiting more synapses to represent the new memory, thus increasing its strength.

Development of ocular dominance columns across rodents and other species: revisiting the concept of critical period plasticity.

The existence of cortical columns, regarded as computational units underlying both lower and higher-order information processing, has long been associated with highly evolved brains, and previous studies suggested their absence in rodents. However, recent discoveries have unveiled the presence of ocular dominance columns (ODCs) in the primary visual cortex (V1) of Long-Evans rats. These domains exhibit continuity from layer 2 through layer 6, confirming their identity as genuine ODCs. Notably, ODCs are also observed in Brown Norway rats, a strain closely related to wild rats, suggesting the physiological relevance of ODCs in natural survival contexts, although they are lacking in albino rats. This discovery has enabled researchers to explore the development and plasticity of cortical columns using a multidisciplinary approach, leveraging studies involving hundreds of individuals-an endeavor challenging in carnivore and primate species. Notably, developmental trajectories differ depending on the aspect under examination: while the distribution of geniculo-cortical afferent terminals indicates matured ODCs even before eye-opening, consistent with prevailing theories in carnivore/primate studies, examination of cortical neuron spiking activities reveals immature ODCs until postnatal day 35, suggesting delayed maturation of functional synapses which is dependent on visual experience. This developmental gap might be recognized as 'critical period' for ocular dominance plasticity in previous studies. In this article, I summarize cross-species differences in ODCs and geniculo-cortical network, followed by a discussion on the development, plasticity, and evolutionary significance of rat ODCs. I discuss classical and recent studies on critical period plasticity in the venue where critical period plasticity might be a component of experience-dependent development. Consequently, this series of studies prompts a paradigm shift in our understanding of species conservation of cortical columns and the nature of plasticity during the classical critical period.

Obesity- and diet-induced plasticity in systems that control eating and energy balance.

In April 2023, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in partnership with the National Institute of Child Health and Human Development, the National Institute on Aging, and the Office of Behavioral and Social Sciences Research, hosted a 2-day online workshop to discuss neural plasticity in energy homeostasis and obesity. The goal was to provide a broad view of current knowledge while identifying research questions and challenges regarding neural systems that control food intake and energy balance. This review includes highlights from the meeting and is intended both to introduce unfamiliar audiences with concepts central to energy homeostasis, feeding, and obesity and to highlight up-and-coming research in these areas that may be of special interest to those with a background in these fields. The overarching theme of this review addresses plasticity within the central and peripheral nervous systems that regulates and influences eating, emphasizing distinctions between healthy and disease states. This is by no means a comprehensive review because this is a broad and rapidly developing area. However, we have pointed out relevant reviews and primary articles throughout, as well as gaps in current understanding and opportunities for developments in the field.

Transcranial direct current stimulation-induced changes in motor cortical connectivity are associated with motor gains following ischemic stroke.

Understanding the response of the injured brain to different transcranial direct current stimulation (tDCS) montages may help explain the variable tDCS treatment results on poststroke motor gains. Cortical connectivity has been found to reflect poststroke motor gains and cortical plasticity, but the changes in connectivity following tDCS remain unknown. We aimed to investigate the relationship between tDCS-induced changes in cortical connectivity and poststroke motor gains. In this study, participants were assigned to receive four tDCS montages (anodal, cathodal, bilateral, and sham) over the primary motor cortex (M1) according to a single-blind, randomized, crossover design. Electroencephalography (EEG) and Jebsen-Taylor hand function test (JTT) were performed before and after the intervention. Motor cortical connectivity was measured using beta-band coherence with the ipsilesional and contralesional M1 as seed regions. Motor gain was evaluated based on the JTT completion time. We examined the relationship between baseline connectivity and clinical characteristics and that between changes in connectivity and motor gains after different tDCS montages. Baseline functional connectivity, motor impairment, and poststroke duration were correlated. High ipsilesional M1-frontal-temporal connectivity was correlated with a good baseline motor status, and increased connectivity was accompanied by good functional improvement following anodal tDCS treatment. Low contralesional M1-frontal-central connectivity was correlated with a good baseline motor status, and decreased connectivity was accompanied by good functional improvement following cathodal tDCS treatment. In conclusion, EEG-based motor cortical connectivity was correlated with stroke characteristics, including motor impairment and poststroke duration, and motor gains induced by anodal and cathodal tDCS.

Early attentional processing and cortical remapping strategies of tactile stimuli in adults with an early and late-onset visual impairment: A cross-sectional study.

Neuroplastic changes appear in people with visual impairment (VI) and they show greater tactile abilities. Improvements in performance could be associated with the development of enhanced early attentional processes based on neuroplasticity. Currently, the various early attentional and cortical remapping strategies that are utilized by people with early (EB) and late-onset blindness (LB) remain unclear. Thus, more research is required to develop effective rehabilitation programs and substitution devices. Our objective was to explore the differences in spatial tactile brain processing in adults with EB, LB and a sighted control group (CG). In this cross-sectional study 27 participants with VI were categorized into EB (n = 14) and LB (n = 13) groups. They were then compared with a CG (n = 15). A vibrotactile device and event-related potentials (ERPs) were utilized while participants performed a spatial tactile line recognition task. The P100 latency and cortical areas of maximal activity were analyzed during the task. The three groups had no statistical differences in P100 latency (p>0.05). All subjects showed significant activation in the right superior frontal areas. Only individuals with VI activated the left superior frontal regions. In EB subjects, a higher activation was found in the mid-frontal and occipital areas. A higher activation of the mid-frontal, anterior cingulate cortex and orbitofrontal zones was observed in LB participants. Compared to the CG, LB individuals showed greater activity in the left orbitofrontal zone, while EB exhibited greater activity in the right superior parietal cortex. The EB had greater activity in the left orbitofrontal region compared to the LB. People with VI may not have faster early attentional processing. EB subjects activate the occipital lobe and right superior parietal cortex during tactile stimulation because of an early lack of visual stimuli and a multimodal information processing. In individuals with LB and EB the orbitofrontal area is activated, suggesting greater emotional processing.

High-frequency repetitive transcranial magnetic stimulation ameliorates memory impairment by inhibiting neuroinflammation in the chronic cerebral hypoperfusion mice.

BACKGROUND: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has been found to ameliorate cognitive impairment. However, the effects of HF-rTMS remain unknown in chronic cerebral hypoperfusion (CCH). AIM: To investigate the effects of HF-rTMS on cognitive improvement and its potential mechanisms in CCH mice. MATERIALS AND METHODS: Daily HF-rTMS therapy was delivered after bilateral carotid stenosis (BCAS) and continued for 14 days. The mice were randomly assigned to three groups: the sham group, the model group, and the HF-rTMS group. The Y maze and the new object recognition test were used to assess cognitive function. The expressions of MAP-2, synapsis, Myelin basic protein(MBP), and brain-derived growth factors (BDNF) were analyzed by immunofluorescence staining and western blot to evaluate neuronal plasticity and white matter myelin regeneration. Nissl staining and the expression of caspase-3, Bax, and Bcl-2 were used to observe neuronal apoptosis. In addition, the activation of microglia and astrocytes were evaluated by fluorescence staining. The inflammation levels of IL-1ß, IL-6, and Tumor Necrosis Factor(TNF)-α were detected by qPCR in the hippocampus of mice in each group. RESULTS: Via behavioral tests, the BCAS mice showed reduced a rate of new object preference and decreased a rate of spontaneous alternations, while HF-rTMS significantly improved hippocampal learning and memory deficits. In addition, the mice in the model group showed decreased levels of MAP-2, synapsis, MBP, and BDNF, while HF-rTMS treatment reversed these effects. As expected, activated microglia and astrocytes increased in the model group, but HF-rTMS treatment suppressed these changes. HF-rTMS decreased BCAS-induced neuronal apoptosis and the expression of pro-apoptotic protein (Caspase-3 and Bax) and increased the expression of anti-apoptotic protein (Bcl-2). In addition, HF-rTMS inhibited the expression of inflammatory cytokines (IL-1ß, IL-6, and TNF-α). CONCLUSIONS: HF-rTMS alleviates cognitive impairment in CCH mice by enhancing neuronal plasticity and inhibiting inflammation, thus serving as a potential method for vascular cognitive impairment.

Co-existence of synaptic plasticity and metastable dynamics in a spiking model of cortical circuits.

Evidence for metastable dynamics and its role in brain function is emerging at a fast pace and is changing our understanding of neural coding by putting an emphasis on hidden states of transient activity. Clustered networks of spiking neurons have enhanced synaptic connections among groups of neurons forming structures called cell assemblies; such networks are capable of producing metastable dynamics that is in agreement with many experimental results. However, it is unclear how a clustered network structure producing metastable dynamics may emerge from a fully local plasticity rule, i.e., a plasticity rule where each synapse has only access to the activity of the neurons it connects (as opposed to the activity of other neurons or other synapses). Here, we propose a local plasticity rule producing ongoing metastable dynamics in a deterministic, recurrent network of spiking neurons. The metastable dynamics co-exists with ongoing plasticity and is the consequence of a self-tuning mechanism that keeps the synaptic weights close to the instability line where memories are spontaneously reactivated. In turn, the synaptic structure is stable to ongoing dynamics and random perturbations, yet it remains sufficiently plastic to remap sensory representations to encode new sets of stimuli. Both the plasticity rule and the metastable dynamics scale well with network size, with synaptic stability increasing with the number of neurons. Overall, our results show that it is possible to generate metastable dynamics over meaningful hidden states using a simple but biologically plausible plasticity rule which co-exists with ongoing neural dynamics.

Hemispheric functional organization, as revealed by naturalistic neuroimaging, in pediatric epilepsy patients with cortical resections.

Functional changes in the pediatric brain following neural injuries attest to remarkable feats of plasticity. Investigations of the neurobiological mechanisms that underlie this plasticity have largely focused on activation in the penumbra of the lesion or in contralesional, homotopic regions. Here, we adopt a whole-brain approach to evaluate the plasticity of the cortex in patients with large unilateral cortical resections due to drug-resistant childhood epilepsy. We compared the functional connectivity (FC) in patients' preserved hemisphere with the corresponding hemisphere of matched controls as they viewed and listened to a movie excerpt in a functional magnetic resonance imaging (fMRI) scanner. The preserved hemisphere was segmented into 180 and 200 parcels using two different anatomical atlases. We calculated all pairwise multivariate statistical dependencies between parcels, or parcel edges, and between 22 and 7 larger-scale functional networks, or network edges, aggregated from the smaller parcel edges. Both the left and right hemisphere-preserved patient groups had widespread reductions in FC relative to matched controls, particularly for within-network edges. A case series analysis further uncovered subclusters of patients with distinctive edgewise changes relative to controls, illustrating individual postoperative connectivity profiles. The large-scale differences in networks of the preserved hemisphere potentially reflect plasticity in the service of maintained and/or retained cognitive function.

Multiple changes in connectivity between buccal ganglia mechanoafferents and motor neurons with different functions after learning that food is inedible in Aplysia.

Changes caused by learning that a food is inedible in Aplysia were examined for fast and slow synaptic connections from the buccal ganglia S1 cluster of mechanoafferents to five followers, in response to repeated stimulus trains. Learning affected only fast connections. For these, unique patterns of change were present in each follower, indicating that learning differentially affects the different branches of the mechanoafferents to their followers. In some followers, there were increases in either excitatory or inhibitory connections, and in others, there were decreases. Changes in connectivity resulted from changes in the amplitude of excitation or inhibition, or as a result of the number of connections, or of both. Some followers also exhibited changes in either within or between stimulus train plasticity as a result of learning. In one follower, changes differed from the different areas of the S1 cluster. The patterns of changes in connectivity were consistent with the behavioral changes produced by learning, in that they would produce an increase in the bias to reject or to release food, and a decrease in the likelihood to respond to food.

CNS/PNS proteoglycans functionalize neuronal and astrocyte niche microenvironments optimizing cellular activity by preserving membrane polarization dynamics, ionic microenvironments, ion fluxes, neuronal activation, and network neurotransductive capacity.

Central and peripheral nervous system (CNS/PNS) proteoglycans (PGs) have diverse functional roles, this study examined how these control cellular behavior and tissue function. The CNS/PNS extracellular matrix (ECM) is a dynamic, responsive, highly interactive, space-filling, cell supportive, stabilizing structure maintaining tissue compartments, ionic microenvironments, and microgradients that regulate neuronal activity and maintain the neuron in an optimal ionic microenvironment. The CNS/PNS contains a high glycosaminoglycan content (60% hyaluronan, HA) and a diverse range of stabilizing PGs. Immobilization of HA in brain tissues by HA interactive hyalectan PGs preserves tissue hydration and neuronal activity, a paucity of HA in brain tissues results in a pro-convulsant epileptic phenotype. Diverse CS, KS, and HSPGs stabilize the blood-brain barrier and neurovascular unit, provide smart gel neurotransmitter neuron vesicle storage and delivery, organize the neuromuscular junction basement membrane, and provide motor neuron synaptic plasticity, and photoreceptor and neuron synaptic functions. PG-HA networks maintain ionic fluxes and microgradients and tissue compartments that contribute to membrane polarization dynamics essential to neuronal activation and neurotransduction. Hyalectans form neuroprotective perineuronal nets contributing to synaptic plasticity, memory, and cognitive learning. Sialoglycoprotein associated with cones and rods (SPACRCAN), an HA binding CSPG, stabilizes the inter-photoreceptor ECM. HSPGs pikachurin and eyes shut stabilize the photoreceptor synapse aiding in phototransduction and neurotransduction with retinal bipolar neurons crucial to visual acuity. This is achieved through Laminin G motifs in pikachurin, eyes shut, and neurexins that interact with the dystroglycan-cytoskeleton-ECM-stabilizing synaptic interconnections, neuronal interactive specificity, and co-ordination of regulatory action potentials in neural networks.

Learning to express reward prediction error-like dopaminergic activity requires plastic representations of time.

The dominant theoretical framework to account for reinforcement learning in the brain is temporal difference learning (TD) learning, whereby certain units signal reward prediction errors (RPE). The TD algorithm has been traditionally mapped onto the dopaminergic system, as firing properties of dopamine neurons can resemble RPEs. However, certain predictions of TD learning are inconsistent with experimental results, and previous implementations of the algorithm have made unscalable assumptions regarding stimulus-specific fixed temporal bases. We propose an alternate framework to describe dopamine signaling in the brain, FLEX (Flexibly Learned Errors in Expected Reward). In FLEX, dopamine release is similar, but not identical to RPE, leading to predictions that contrast to those of TD. While FLEX itself is a general theoretical framework, we describe a specific, biophysically plausible implementation, the results of which are consistent with a preponderance of both existing and reanalyzed experimental data.

Selective consolidation of learning and memory via recall-gated plasticity.

In a variety of species and behavioral contexts, learning and memory formation recruits two neural systems, with initial plasticity in one system being consolidated into the other over time. Moreover, consolidation is known to be selective; that is, some experiences are more likely to be consolidated into long-term memory than others. Here, we propose and analyze a model that captures common computational principles underlying such phenomena. The key component of this model is a mechanism by which a long-term learning and memory system prioritizes the storage of synaptic changes that are consistent with prior updates to the short-term system. This mechanism, which we refer to as recall-gated consolidation, has the effect of shielding long-term memory from spurious synaptic changes, enabling it to focus on reliable signals in the environment. We describe neural circuit implementations of this model for different types of learning problems, including supervised learning, reinforcement learning, and autoassociative memory storage. These implementations involve synaptic plasticity rules modulated by factors such as prediction accuracy, decision confidence, or familiarity. We then develop an analytical theory of the learning and memory performance of the model, in comparison to alternatives relying only on synapse-local consolidation mechanisms. We find that recall-gated consolidation provides significant advantages, substantially amplifying the signal-to-noise ratio with which memories can be stored in noisy environments. We show that recall-gated consolidation gives rise to a number of phenomena that are present in behavioral learning paradigms, including spaced learning effects, task-dependent rates of consolidation, and differing neural representations in short- and long-term pathways.

Non-Hebbian plasticity transforms transient experiences into lasting memories.

The dominant models of learning and memory, such as Hebbian plasticity, propose that experiences are transformed into memories through input-specific synaptic plasticity at the time of learning. However, synaptic plasticity is neither strictly input-specific nor restricted to the time of its induction. The impact of such forms of non-Hebbian plasticity on memory has been difficult to test, and hence poorly understood. Here, we demonstrate that synaptic manipulations can deviate from the Hebbian model of learning, yet produce a lasting memory. First, we established a weak associative conditioning protocol in mice, where optogenetic stimulation of sensory thalamic input to the amygdala was paired with a footshock, but no detectable memory was formed. However, when the same input was potentiated minutes before or after, or even 24 hr later, the associative experience was converted into a lasting memory. Importantly, potentiating an independent input to the amygdala minutes but not 24 hr after the pairing produced a lasting memory. Thus, our findings suggest that the process of transformation of a transient experience into a memory is neither restricted to the time of the experience nor to the synapses triggered by it; instead, it can be influenced by past and future events.

Cortical plasticity is associated with blood-brain barrier modulation.

Brain microvessels possess the unique properties of a blood-brain barrier (BBB), tightly regulating the passage of molecules from the blood to the brain neuropil and vice versa. In models of brain injury, BBB dysfunction and the associated leakage of serum albumin to the neuropil have been shown to induce pathological plasticity, neuronal hyper-excitability, and seizures. The effect of neuronal activity on BBB function and whether it plays a role in plasticity in the healthy brain remain unclear. Here we show that neuronal activity induces modulation of microvascular permeability in the healthy brain and that it has a role in local network reorganization. Combining simultaneous electrophysiological recording and vascular imaging with transcriptomic analysis in rats, and functional and BBB-mapping MRI in human subjects, we show that prolonged stimulation of the limb induces a focal increase in BBB permeability in the corresponding somatosensory cortex that is associated with long-term synaptic plasticity. We further show that the increased microvascular permeability depends on neuronal activity and involves caveolae-mediated transcytosis and transforming growth factor ß signaling. Our results reveal a role of BBB modulation in cortical plasticity in the healthy brain, highlighting the importance of neurovascular interactions for sensory experience and learning.

Contributions of cortical neuron firing patterns, synaptic connectivity, and plasticity to task performance.

Neuronal responses during behavior are diverse, ranging from highly reliable 'classical' responses to irregular 'non-classically responsive' firing. While a continuum of response properties is observed across neural systems, little is known about the synaptic origins and contributions of diverse responses to network function, perception, and behavior. To capture the heterogeneous responses measured from auditory cortex of rodents performing a frequency recognition task, we use a novel task-performing spiking recurrent neural network incorporating spike-timing-dependent plasticity. Reliable and irregular units contribute differentially to task performance via output and recurrent connections, respectively. Excitatory plasticity shifts the response distribution while inhibition constrains its diversity. Together both improve task performance with full network engagement. The same local patterns of synaptic inputs predict spiking response properties of network units and auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus, diverse neural responses contribute to network function and emerge from synaptic plasticity rules.

Electrical Stimulation: How It Works and How to Apply It.

Electrical stimulation is emerging as a perioperative strategy to improve peripheral nerve regeneration and enhance functional recovery. Despite decades of research, new insights into the complex multifaceted mechanisms of electrical stimulation continue to emerge, providing greater understanding of the neurophysiology of nerve regeneration. In this study, we summarize what is known about how electrical stimulation modulates the molecular cascades and cellular responses innate to nerve injury and repair, and the consequential effects on axonal growth and plasticity. Further, we discuss how electrical stimulation is delivered in preclinical and clinical studies and identify knowledge gaps that may provide opportunities for optimization.

Astrocytes enhance plasticity response during reversal learning.

Astrocytes play a key role in the regulation of synaptic strength and are thought to orchestrate synaptic plasticity and memory. Yet, how specifically astrocytes and their neuroactive transmitters control learning and memory is currently an open question. Recent experiments have uncovered an astrocyte-mediated feedback loop in CA1 pyramidal neurons which is started by the release of endocannabinoids by active neurons and closed by astrocytic regulation of the D-serine levels at the dendrites. D-serine is a co-agonist for the NMDA receptor regulating the strength and direction of synaptic plasticity. Activity-dependent D-serine release mediated by astrocytes is therefore a candidate for mediating between long-term synaptic depression (LTD) and potentiation (LTP) during learning. Here, we show that the mathematical description of this mechanism leads to a biophysical model of synaptic plasticity consistent with the phenomenological model known as the BCM model. The resulting mathematical framework can explain the learning deficit observed in mice upon disruption of the D-serine regulatory mechanism. It shows that D-serine enhances plasticity during reversal learning, ensuring fast responses to changes in the external environment. The model provides new testable predictions about the learning process, driving our understanding of the functional role of neuron-glia interaction in learning.