Changes In Synaptic Connectivity Research Articles

Elucidating the molecular symphony: unweaving the transcriptional & epigenetic pathways underlying neuroplasticity in opioid dependence and withdrawal.

The persistent use of opioids leads to profound changes in neuroplasticity of the brain, contributing to the emergence and persistence of addiction. However, chronic opioid use disrupts the delicate balance of the reward system in the brain, leading to neuroadaptations that underlie addiction. Chronic cocaine usage leads to synchronized alterations in gene expression, causing modifications in the Nucleus Accumbens (NAc), a vital part of the reward system of the brain. These modifications assist in the development of maladaptive behaviors that resemble addiction. Neuroplasticity in the context of addiction involves changes in synaptic connectivity, neuronal morphology, and molecular signaling pathways. Drug-evoked neuroplasticity in opioid addiction and withdrawal represents a complicated interaction between environmental, genetic, and epigenetic factors. Identifying specific transcriptional and epigenetic targets that can be modulated to restore normal neuroplasticity without disrupting essential physiological processes is a critical consideration. The discussion in this article focuses on the transcriptional aspects of drug-evoked neuroplasticity, emphasizing the role of key transcription factors, including cAMP response element-binding protein (CREB), ΔFosB, NF-kB, Myocyte-enhancing factor 2 (MEF2), Methyl-CpG binding protein 2 (MeCP2), E2F3a, and FOXO3a. These factors regulate gene expression and lead to the neuroadaptive changes observed in addiction and withdrawal. Epigenetic regulation, which involves modifying gene accessibility by controlling these structures, has been identified as a critical component of addiction development. By unraveling these complex molecular processes, this study provides valuable insights that may pave the way for future therapeutic interventions targeting the mechanisms underlying addiction and withdrawal.

The function of juvenile-adult transition axis in female sexual receptivity of Drosophila melanogaster.

Female sexual receptivity is essential for reproduction of a species. Neuropeptides play the main role in regulating female receptivity. However, whether neuropeptides regulate female sexual receptivity during the neurodevelopment is unknown. Here, we found the peptide hormone prothoracicotropic hormone (PTTH), which belongs to the insect PG (prothoracic gland) axis, negatively regulated virgin female receptivity through ecdysone during neurodevelopment in Drosophila melanogaster. We identified PTTH neurons as doublesex-positive neurons, they regulated virgin female receptivity before the metamorphosis during the third-instar larval stage. PTTH deletion resulted in the increased EcR-A expression in the whole newly formed prepupae. Furthermore, the ecdysone receptor EcR-A in pC1 neurons positively regulated virgin female receptivity during metamorphosis. The decreased EcR-A in pC1 neurons induced abnormal morphological development of pC1 neurons without changing neural activity. Among all subtypes of pC1 neurons, the function of EcR-A in pC1b neurons was necessary for virgin female copulation rate. These suggested that the changes of synaptic connections between pC1b and other neurons decreased female copulation rate. Moreover, female receptivity significantly decreased when the expression of PTTH receptor Torso was reduced in pC1 neurons. This suggested that PTTH not only regulates female receptivity through ecdysone but also through affecting female receptivity associated neurons directly. The PG axis has similar functional strategy as the hypothalamic-pituitary-gonadal axis in mammals to trigger the juvenile-adult transition. Our work suggests a general mechanism underlying which the neurodevelopment during maturation regulates female sexual receptivity.

PI3K couples long-term synaptic potentiation with cofilin recruitment and actin polymerization in dendritic spines via its regulatory subunit p85α

Long-term synaptic plasticity is typically associated with morphological changes in synaptic connections. However, the molecular mechanisms coupling functional and structural aspects of synaptic plasticity are still poorly defined. The catalytic activity of type I phosphoinositide-3-kinase (PI3K) is required for specific forms of synaptic plasticity, such as NMDA receptor-dependent long-term potentiation (LTP) and mGluR-dependent long-term depression (LTD). On the other hand, PI3K signaling has been linked to neuronal growth and synapse formation. Consequently, PI3Ks are promising candidates to coordinate changes in synaptic strength with structural remodeling of synapses. To investigate this issue, we targeted individual regulatory subunits of type I PI3Ks in hippocampal neurons and employed a combination of electrophysiological, biochemical and imaging techniques to assess their role in synaptic plasticity. We found that a particular regulatory isoform, p85α, is selectively required for LTP. This specificity is based on its BH domain, which engages the small GTPases Rac1 and Cdc42, critical regulators of the actin cytoskeleton. Moreover, cofilin, a key regulator of actin dynamics that accumulates in dendritic spines after LTP induction, failed to do so in the absence of p85α or when its BH domain was overexpressed as a dominant negative construct. Finally, in agreement with this convergence on actin regulatory mechanisms, the presence of p85α in the PI3K complex determined the extent of actin polymerization in dendritic spines during LTP. Therefore, this study reveals a molecular mechanism linking structural and functional synaptic plasticity through the coordinate action of PI3K catalytic activity and a specific isoform of the regulatory subunits.

Microglia: The Drunken Gardeners of Early Adversity.

Early life adversity (ELA) is a heterogeneous group of negative childhood experiences that can lead to abnormal brain development and more severe psychiatric, neurological, and medical conditions in adulthood. According to the immune hypothesis, ELA leads to an abnormal immune response characterized by high levels of inflammatory cytokines. This abnormal immune response contributes to more severe negative health outcomes and a refractory response to treatment in individuals with a history of ELA. Here, we examine this hypothesis in the context of recent rodent studies that focus on the impact of ELA on microglia, the resident immune cells in the brain. We review recent progress in our ability to mechanistically link molecular alterations in microglial function during a critical period of development with changes in synaptic connectivity, cognition, and stress reactivity later in life. We also examine recent research showing that ELA induces long-term alterations in microglial inflammatory response to "secondary hits" such as traumatic brain injury, substance use, and exposure to additional stress in adulthood. We conclude with a discussion on future directions and unresolved questions regarding the signals that modify microglial function and the clinical significance of rodent studies for humans.

Neural ageing and synaptic plasticity: prioritizing brain health in healthy longevity.

Ageing is characterized by a gradual decline in the efficiency of physiological functions and increased vulnerability to diseases. Ageing affects the entire body, including physical, mental, and social well-being, but its impact on the brain and cognition can have a particularly significant effect on an individual's overall quality of life. Therefore, enhancing lifespan and physical health in longevity studies will be incomplete if cognitive ageing is over looked. Promoting successful cognitive ageing encompasses the objectives of mitigating cognitive decline, as well as simultaneously enhancing brain function and cognitive reserve. Studies in both humans and animal models indicate that cognitive decline related to normal ageing and age-associated brain disorders are more likely linked to changes in synaptic connections that form the basis of learning and memory. This activity-dependent synaptic plasticity reorganises the structure and function of neurons not only to adapt to new environments, but also to remain robust and stable over time. Therefore, understanding the neural mechanisms that are responsible for age-related cognitive decline becomes increasingly important. In this review, we explore the multifaceted aspects of healthy brain ageing with emphasis on synaptic plasticity, its adaptive mechanisms and the various factors affecting the decline in cognitive functions during ageing. We will also explore the dynamic brain and neuroplasticity, and the role of lifestyle in shaping neuronal plasticity.

Phase Delays between Mouse Globus Pallidus Neurons Entrained by Common Oscillatory Drive Arise from Their Intrinsic Properties, Not Their Coupling.

A hallmark of Parkinson's disease is the appearance of correlated oscillatory discharge throughout the cortico-basal ganglia (BG) circuits. In the primate globus pallidus (GP), where the discharge of GP neurons is normally uncorrelated, pairs of GP neurons exhibit oscillatory spike correlations with a broad distribution of pairwise phase delays in experimental parkinsonism. The transition to oscillatory correlations is thought to indicate the collapse of the normally segregated information channels traversing the BG. The large phase delays are thought to reflect pathological changes in synaptic connectivity in the BG. Here we study the structure and phase delays of spike correlations measured from neurons in the mouse external GP (GPe) subjected to identical 1-100 Hz sinusoidal drive but recorded in separate experiments. First, we found that spectral modes of a GPe neuron's empirical instantaneous phase response curve (iPRC) elucidate at what phases of the oscillatory drive the GPe neuron locks when it is entrained and the distribution of phases at which it spikes when it is not. Then, we show that in this case the pairwise spike cross-correlation equals the cross-correlation function of these spike phase distributions. Finally, we show that the distribution of GPe phase delays arises from the diversity of iPRCs and is broadened when the neurons become entrained. Modeling GPe networks with realistic intranuclear connectivity demonstrates that the connectivity decorrelates GPe neurons without affecting phase delays. Thus, common oscillatory input gives rise to GPe correlations whose structure and pairwise phase delays reflect their intrinsic properties captured by their iPRCs.

Wired together, change together: Spike timing modifies transmission in converging assemblies.

The precise timing of neuronal spikes may lead to changes in synaptic connectivity and is thought to be crucial for learning and memory. However, the effect of spike timing on neuronal connectivity in the intact brain remains unknown. Using closed-loop optogenetic stimulation in CA1 of freely moving mice, we generated unique spike patterns between presynaptic pyramidal cells (PYRs) and postsynaptic parvalbumin (PV)-immunoreactive cells. The stimulation led to spike transmission changes that occurred together across all presynaptic PYRs connected to the same postsynaptic PV cell. The precise timing of all presynaptic and postsynaptic cell spikes affected transmission changes. These findings reveal an unexpected plasticity mechanism, in which the spike timing of an entire cell assembly has a more substantial impact on effective connectivity than that of individual cell pairs.

Changes in synaptic inputs to dI3 INs and MNs after complete transection in adult mice.

Spinal cord injury (SCI) is a debilitating condition that disrupts the communication between the brain and the spinal cord. Several studies have sought to determine how to revive dormant spinal circuits caudal to the lesion to restore movements in paralyzed patients. So far, recovery levels in human patients have been modest at best. In contrast, animal models of SCI exhibit more recovery of lost function. Previous work from our lab has identified dI3 interneurons as a spinal neuron population central to the recovery of locomotor function in spinalized mice. We seek to determine the changes in the circuitry of dI3 interneurons and motoneurons following SCI in adult mice. After a complete transection of the spinal cord at T9-T11 level in transgenic Isl1:YFP mice and subsequent treadmill training at various time points of recovery following surgery, we examined changes in three key circuits involving dI3 interneurons and motoneurons: (1) Sensory inputs from proprioceptive and cutaneous afferents, (2) Presynaptic inhibition of sensory inputs, and (3) Central excitatory glutamatergic synapses from spinal neurons onto dI3 INs and motoneurons. Furthermore, we examined the possible role of treadmill training on changes in synaptic connectivity to dI3 interneurons and motoneurons. Our data suggests that VGLUT1+ inputs to dI3 interneurons decrease transiently or only at later stages after injury, whereas levels of VGLUT1+ remain the same for motoneurons after injury. Levels of VGLUT2+ inputs to dI3 INs and MNs may show transient increases but fall below levels seen in sham-operated mice after a period of time. Levels of presynaptic inhibition to VGLUT1+ inputs to dI3 INs and MNs can rise shortly after SCI, but those increases do not persist. However, levels of presynaptic inhibition to VGLUT1+ inputs never fell below levels observed in sham-operated mice. For some synaptic inputs studied, levels were higher in spinal cord-injured animals that received treadmill training, but these increases were observed only at some time points. These results suggest remodeling of spinal circuits involving spinal interneurons that have previously been implicated in the recovery of locomotor function after spinal cord injury in mice.

Potential Roles of m6A and FTO in Synaptic Connectivity and Major Depressive Disorder

RNA modifications known as epitranscriptomics have emerged as a novel layer of transcriptomic regulation. Like the well-studied epigenetic modifications characterized in DNA and on histone-tails, they have been shown to regulate activity-dependent gene expression and play a vital role in shaping synaptic connections in response to external stimuli. Among the hundreds of known RNA modifications, N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes. Through recognition of its binding proteins, m6A can regulate various aspects of mRNA metabolism and is essential for maintaining higher brain functions. Indeed, m6A is highly enriched in synapses and is involved in neuronal plasticity, learning and memory, and adult neurogenesis. m6A can also respond to environmental stimuli, suggesting an important role in linking molecular and behavioral stress. This review summarizes key findings from fields related to major depressive disorder (MDD) including stress and learning and memory, which suggest that activity-dependent m6A changes may, directly and indirectly, contribute to synaptic connectivity changes underlying MDD. Furthermore, we will highlight the roles of m6A and FTO, a m6A eraser, in the context of depressive-like behaviors. Although we have only begun to explore m6A in the context of MDD and psychiatry, elucidating a link between m6A and MDD presents a novel molecular mechanism underlying MDD pathogenesis.

Generalized extinction of fear memory depends on co-allocation of synaptic plasticity in dendrites

Memories can be modified by new experience in a specific or generalized manner. Changes in synaptic connections are crucial for memory storage, but it remains unknown how synaptic changes associated with different memories are distributed within neuronal circuits and how such distributions affect specific or generalized modification by novel experience. Here we show that fear conditioning with two different auditory stimuli (CS) and footshocks (US) induces dendritic spine elimination mainly on different dendritic branches of layer 5 pyramidal neurons in the mouse motor cortex. Subsequent fear extinction causes CS-specific spine formation and extinction of freezing behavior. In contrast, spine elimination induced by fear conditioning with >2 different CS-USs often co-exists on the same dendritic branches. Fear extinction induces CS-nonspecific spine formation and generalized fear extinction. Moreover, activation of somatostatin-expressing interneurons increases the occurrence of spine elimination induced by different CS-USs on the same dendritic branches and facilitates the generalization of fear extinction. These findings suggest that specific or generalized modification of existing memories by new experience depends on whether synaptic changes induced by previous experiences are segregated or co-exist at the level of individual dendritic branches.

Changes in the structure of synaptic intercellular contacts in focal brain lesions

Purpose: to evaluate changes in the structure of synaptic contacts in various types of focal brain pathology. Materials and methods. The results of treatment of 40 cases of supratentorial focal lesions of the brain (FLB) were retrospectively evaluated. The cases are divided into groups: 30 gliomas of various degrees of malignancy and 5 consequences of TBI, 5 epilepsy. All patients underwent surgical interventions. The synaptic plasticity of axo-dendritic and axo-spiny asymmetric synapses of neurons of the VI-VII layers of the frontotemporal cortex was studied by electron microscopy. Morphometric analysis was carried out on a computer image analyzer САИ-01АВН using the software "Kappa opto-electronics GmbH" using the STATISTICA 7 program package. The results. It was established that the density of synapses decreased in glioblastomas (GB) and craniocerebral injury (ССІ). Qualitative changes demonstrate the plasticity of architectonics of synapse, in particular due to the increase in the number of perforated synaptic contacts. Maximum thickening and diffuse stratification of the postsynaptic seal indicates a violation of the functional capacity of the postsynaptic component of the contacts. A decrease in the number of synaptic vesicles was revealed in ССІ and GB, with their rearrangement, which is probably a manifestation of synaptic dysfunction. The latter proves the irreversibility of destructive local changes and is unfavorable criterion. The risk of the formation of destructive-degenerative changes in the synaptic apparatus is 7.64 times higher in DA, 3.17 times higher in GB, and 17.31 times higher in ССІ compared to cases of epilepsy, with GB significantly increases by 13.5 times compared to DA. Therefore, the assessment of the structural features of neuroplasticity should take into account the morphogenesis of the BM in comparison with clinical data Conclusions. In the zones of invasive growth of gliomas of various degrees of malignancy and in ССІ and epilepsy, the indicators of synaptic plasticity differ statistically significantly. The density of placement of synapses is lower in GB and ССІ. The probability of non-reversibility of destructive-degenerative changes of synapses according to the number of SVs in FLB correlates with the degree of glioma differentiation with a sensitivity of 81.0% and a specificity of 76.0%. According to the structural changes of synaptic connections in tumors, probable differences between the variants have been proven: GB and DA, the sensitivity of the discriminant model is 85.0%, the specificity is 74.0%, which is an indirect evidence of the growth rate of the tumor mass and its destructive effect on the surrounding brain matter. The obtained results are important in assessing the prognosis of the further course of the disease.

Small, correlated changes in synaptic connectivity may facilitate rapid motor learning

Animals rapidly adapt their movements to external perturbations, a process paralleled by changes in neural activity in the motor cortex. Experimental studies suggest that these changes originate from altered inputs (Hinput) rather than from changes in local connectivity (Hlocal), as neural covariance is largely preserved during adaptation. Since measuring synaptic changes in vivo remains very challenging, we used a modular recurrent neural network to qualitatively test this interpretation. As expected, Hinput resulted in small activity changes and largely preserved covariance. Surprisingly given the presumed dependence of stable covariance on preserved circuit connectivity, Hlocal led to only slightly larger changes in activity and covariance, still within the range of experimental recordings. This similarity is due to Hlocal only requiring small, correlated connectivity changes for successful adaptation. Simulations of tasks that impose increasingly larger behavioural changes revealed a growing difference between Hinput and Hlocal, which could be exploited when designing future experiments.

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies.

Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).

Regulatory effects of gradient microtopographies on synapse formation and neurite growth in hippocampal neurons

Among approaches aiming toward functional nervous system restoration, those implementing microfabrication techniques allow the manufacture of platforms with distinct geometry where neurons can develop and be guided to form patterned connections in vitro. The interplay between neuronal development and the microenvironment, shaped by the physical limitations, remains largely unknown. Therefore, it is crucial to have an efficient way to quantify neuronal morphological changes induced by physical or contact guidance of the microenvironment. In this study, we first devise and assess a method to prepare anisotropic, gradient poly(dimethylsiloxane) micro-ridge/groove arrays featuring variable local pattern width. We then demonstrate the ability of this single substrate to simultaneously profile the morphologcial and synaptic connectivity changes of primary cultured hippocampal neurons reacting to variable physical conditons, throughout neurodevelopment, in vitro. The gradient microtopography enhanced adhesion within microgrooves, increasing soma density with decreasing pattern width. Decreasing pattern width also reduced dendritic arborization and increased preferential axon growth. Finally, decreasing pattern geometry inhibited presynaptic puncta architecture. Collectively, a method to examine structural development and connectivity in response to physical stimuli is established, and potentially provides insight into microfabricated geometries which promote neural regeneration and repair.

Diffusion tensor imaging reveals brain structure changes in dogs after spinal cord injury.

Based on the Wallerian degeneration in the spinal cord pathways, the changes in synaptic connections, and the spinal cord-related cellular responses that alter the cellular structure of the brain, we presumed that brain diffusion tensor imaging (DTI) parameters may change after spinal cord injury. However, the dynamic changes in DTI parameters remain unclear. We established a Beagle dog model of T10 spinal cord contusion and performed DTI of the injured spinal cord. We found dynamic changes in DTI parameters in the cerebral peduncle, posterior limb of the internal capsule, pre- and postcentral gyri of the brain within 12 weeks after spinal cord injury. We then performed immunohistochemistry to detect the expression of neurofilament heavy polypeptide (axonal marker), glial fibrillary acidic protein (glial cell marker), and NeuN (neuronal marker). We found that these pathological changes were consistent with DTI parameter changes. These findings suggest that DTI can display brain structure changes after spinal cord injury.

Ion-Movement-Based Synaptic Device for Brain-Inspired Computing.

As the amount of data has grown exponentially with the advent of artificial intelligence and the Internet of Things, computing systems with high energy efficiency, high scalability, and high processing speed are urgently required. Unlike traditional digital computing, which suffers from the von Neumann bottleneck, brain-inspired computing can provide efficient, parallel, and low-power computation based on analog changes in synaptic connections between neurons. Synapse nodes in brain-inspired computing have been typically implemented with dozens of silicon transistors, which is an energy-intensive and non-scalable approach. Ion-movement-based synaptic devices for brain-inspired computing have attracted increasing attention for mimicking the performance of the biological synapse in the human brain due to their low area and low energy costs. This paper discusses the recent development of ion-movement-based synaptic devices for hardware implementation of brain-inspired computing and their principles of operation. From the perspective of the device-level requirements for brain-inspired computing, we address the advantages, challenges, and future prospects associated with different types of ion-movement-based synaptic devices.

Anatomical and Functional Differences in the Sex-Shared Neurons of the Nematode C. elegans.

Studies on sexual dimorphism in the structure and function of the nervous system have been pivotal to understanding sex differences in behavior. Such studies, especially on invertebrates, have shown the importance of neurons specific to one sex (sex-specific neurons) in shaping sexually dimorphic neural circuits. Nevertheless, recent studies using the nematode C. elegans have revealed that the common neurons that exist in both sexes (sex-shared neurons) also play significant roles in generating sex differences in the structure and function of neural circuits. Here, we review the anatomical and functional differences in the sex-shared neurons of C. elegans. These sexually dimorphic characteristics include morphological differences in neurite projection or branching patterns with substantial changes in synaptic connectivity, differences in synaptic connections without obvious structural changes, and functional modulation in neural circuits with no or minimal synaptic connectivity changes. We also cover underlying molecular mechanisms whereby these sex-shared neurons contribute to the establishment of sexually dimorphic circuits during development and function differently between the sexes.

Transition dynamics and optogenetic controls of generalized periodic epileptiform discharges

This paper aims to analyze possible mechanisms underlying the generation of generalized periodic epileptiform discharges (GPEDs), especially to design targeted optogenetic regulation strategies. First and foremost, inspired by existing physiological experiments, we propose a new computational framework by introducing a second inhibitory neuronal population and related synaptic connections into the classic Liley mean field model. The improved model can simulate the basic normal and abnormal brain activities mentioned in previous studies, but much to our relief, it perfectly reproduces some types of GPEDs that match the clinical records. Specifically, results show that disinhibitory synaptic connections between inhibitory interneuronal populations are closely related to the occurrence, transition and termination of GPEDs, including delaying the occurrence of GPEDs caused by the excitatory AMPAergic autapses and regulating the transition process of GPEDs bidirectionally, which support the conjecture that selective changes of synaptic connections can trigger GPEDs. Additionally, we creatively offer six optogenetic strategies with dual targets. They can all control GPEDs well, just as experiments reveal that optogenetic stimulation of inhibitory interneurons can suppress abnormal activities in epilepsy or other brain diseases. More importantly, 1:1 coordinated reset stimulation with one period rest is concluded as the optimal strategy after taking into account the energy consumption and control effect. Hope these results provide feasible references for pathophysiological mechanisms of GPEDs.

Transcranial focused ultrasound induces sustained synaptic plasticity in rat hippocampus

Transcranial focused ultrasound (tFUS) neuromodulation provides a promising emerging non-invasive therapy for the treatment of neurological disorders. Many studies have demonstrated the ability of tFUS to elicit transient changes in neural responses. However, the ability of tFUS to induce sustained changes need to be carefully examined. In this study, we use the long-term potentiation/long term depression (LTP/LTD) model in the rat hippocampus, the medial perforant path (mPP) to dentate gyrus (DG) pathway, to explore whether tFUS is capable of encoding frequency specific information to induce plasticity. Single-element focused transducers were used for tFUS stimulation with ultrasound fundamental frequency of 0.5 MHz and nominal focal distance of 38 mm tFUS stimulation is directed to mPP. Measurement of synaptic connectivity is achieved through the slope of field excitatory post synaptic potentials (fEPSPs), which are elicited using bipolar electrical stimulation electrodes and recorded at DG using extracellular electrodes to quantify degree of plasticity. We applied pulsed tFUS stimulation with total duration of 5 min, with 5 levels of pulse repetition frequencies each administered at 50 Hz sonication frequency at the mPP. Baseline fEPSP is recorded 10 min prior, and 30+ minutes after tFUS administration. In N = 16 adult wildtype rats, we observed sustained depression of fEPSP slope after 5 min of tFUS focused at the presynaptic field mPP. Across all PRFs, no significant difference in maximum fEPSP slope change was observed, average tFUS induced depression level was observed at 19.6%. When compared to low frequency electrical stimulation (LFS) of 1 Hz delivered to the mPP, the sustained changes induced by tFUS stimulation show no statistical difference to LFS for up to 24 min after tFUS stimulation. When both the maximum depression effects and the duration of sustained effects are both taken into account, PRF 3 kHz can induce significantly larger effects than other PRFs tested. tFUS stimulation is measured with a spatial-peak pressure amplitude of 99 kPa, translating to an estimation of 0.43 °C temperature increase when assuming no loss of heat. The results suggest the ability of tFUS to encode sustained changes in synaptic connectivity through mechanism which are unlikely to involve thermal changes.

Sleep promotes the formation of dendritic filopodia and spines near learning-inactive existing spines

Changes in synaptic connections are believed to underlie long-term memory storage. Previous studies have suggested that sleep is important for synapse formation after learning, but how sleep is involved in the process of synapse formation remains unclear. To address this question, we used transcranial two-photon microscopy to investigate the effect of postlearning sleep on the location of newly formed dendritic filopodia and spines of layer 5 pyramidal neurons in the primary motor cortex of adolescent mice. We found that newly formed filopodia and spines were partially clustered with existing spines along individual dendritic segments 24 h after motor training. Notably, posttraining sleep was critical for promoting the formation of dendritic filopodia and spines clustered with existing spines within 8 h. A fraction of these filopodia was converted into new spines and contributed to clustered spine formation 24 h after motor training. This sleep-dependent spine formation via filopodia was different from retraining-induced new spine formation, which emerged from dendritic shafts without prior presence of filopodia. Furthermore, sleep-dependent new filopodia and spines tended to be formed away from existing spines that were active at the time of motor training. Taken together, these findings reveal a role of postlearning sleep in regulating the number and location of new synapses via promoting filopodial formation.