Brain Regions Research Articles

Connectivity Reveals the Relationships between Human Brain Areas Associated with High-Level Linguistic Processing and Macaque Brain Areas

Cross-species research has advanced human understanding of brain regions, with cross-species comparisons using magnetic resonance imaging technology becoming increasingly common. Currently, cross-species research on human language regions has primarily focused on traditional brain areas such as the Broca region. While some studies have indicated that human language function also involves other language regions, the corresponding relationships between these brain regions in humans and macaques remain unclear. This study calculated the strength of the connections between the high-level language processing regions in human and macaque brains, identified homologous target areas based on the structural connections of white-matter fiber bundles, and compared the connectivity profiles of both species. The results of the experiment demonstrated that macaques possess brain regions which exhibit connectivity patterns resembling those found in human high-level language processing regions. This discovery suggests that while the function of a human brain region is specialized, it still maintains a structural connectivity similar to that seen in macaques.

Comparisons of the amplitude of low-frequency fluctuation and functional connectivity in major depressive disorder and social anxiety disorder: A resting-state fMRI study

BackgroundStudies comparing the brain functions of major depressive disorder (MDD) and social anxiety disorder (SAD) at the regional and network levels remain scarce. This study aimed to elucidate their pathogenesis using neuroimaging techniques and explore biomarkers that can differentiate these disorders. MethodsResting-state fMRI data were collected from 48 patients with MDD, 41 patients with SAD, and 82 healthy controls. Differences in the amplitude of low-frequency fluctuations (ALFF) among the three groups were examined to identify regions showing abnormal regional spontaneous activity. A seed-based functional connectivity (FC) analysis was conducted using ALFF results as seeds and different connections were identified between regions showing abnormal local spontaneous activity and other regions. The correlation between abnormal brain function and clinical symptoms was analyzed. ResultsPatients with MDD and SAD exhibited similar abnormal ALFF and FC in several brain regions; notably, FC between the right superior frontal gyrus (SFG) and the right posterior supramarginal gyrus (pSMG) in patients with SAD was negatively correlated with depressive symptoms. Furthermore, patients with MDD showed higher ALFF in the right SFG than HCs and those with SAD. LimitationPotential effects of medications, comorbidities, and data type could not be ignored. ConclusionMDD and SAD showed common and distinct aberrant brain function patterns at the regional and network levels. At the regional level, we found that the ALFF in the right SFG was different between patients with MDD and those with SAD. At the network level, we did not find any differences between these disorders.

Electric field temporal interference stimulation of neurons in vitro.

Electrical stimulation (ES) techniques, such as deep brain and transcranial electrical stimulation, have shown promise in alleviating the symptoms of depression and other neurological disorders in vivo. A new noninvasive ES method called temporal interference stimulation (TIS), possesses great potential as it can be used to steer the stimulation and possibly selectively modulate different brain regions. To study TIS in a controlled environment, we successfully established an in vitro 'TIS on a chip' setup using rat cortical neurons on microelectrode arrays (MEAs) in combination with a current stimulator. We validated the developed TIS system and demonstrated the spatial steerability of the stimulation by direct electric field measurements in the chip setup. We stimulated cultures of rat cortical neurons at 28 days in vitro (DIV) by two-channel stimulation delivering 1) TIS at 653 Hz and 643 Hz, resulting in a 10 Hz frequency envelope, 2) low-frequency stimulation (LFS) at 10 Hz and 3) high-frequency stimulation (HFS) at 653 Hz. Unstimulated cultures were used as control/sham. We observed the differences in the electric field strengths during TIS, HFS, and LFS. Moreover, HFS and LFS had the smallest effects on neuronal activity. Instead, TIS elicited neuronal electrophysiological responses, especially 24 hours after stimulation. Our 'TIS on a chip' approach eludicates the applicability of TIS as a method to modulate neuronal electrophysiological activity. The TIS on a chip approach provides spatially steerable stimuli while mitigating the effects of high stimulus fields near the stimulation electrodes. Thus, the approach opens new avenues for stimulation on a chip applications, allowing the study of neuronal responses to gain insights into the potential clinical applications of TIS in treating various brain disorders.

Synaptic connectivity and electrophysiological properties of the nucleus of the lateral olfactory tract.

The sense of smell is tightly linked to emotions, a link that is thought to rely on the direct synaptic connections between the olfactory bulb and nuclei of the amygdala. However, there are multiple pathways projecting olfactory information to the amygdala and their unique functions are unknown. Among them, is the pathway via the nucleus of the lateral olfactory tract (NLOT) that receives input from olfactory regions and projects to the basolateral amygdala. NLOT has been very little studied and consequentially its function is unknown. Furthermore, formulation of informed hypotheses about NLOT function is at this stage limited by the lack of knowledge about its connectivity and physiological properties. Here, we used virus-based tracing methods to systematically reveal inputs into NLOT, as well as NLOT projection targets in mice of both sexes. We found that the NLOT is interconnected with several olfactory brain regions and with the basolateral amygdala. Some of these connections were reciprocal, and some showed unique interhemispheric patterns. We tested the excitable properties of NLOT neurons and the properties of each of the major synaptic inputs. We found that the NLOT receives powerful input from piriform cortex, tenia tecta, and the basolateral amygdala, but only very weak input from the olfactory bulb. When input crosses threshold, NLOT neurons respond with calcium-dependent bursts of action potentials. We hypothesize that this integration of olfactory and amygdalar inputs serves behaviors that combine smell and emotion.Significance statement Despite the well-known anatomical connections between olfactory and amygdalar brain regions, their physiological properties remain largely understudied. One major pathway by which olfactory and amygdalar signals interact, is via the nucleus of the lateral olfactory tract (NLOT). NLOT has been little studied and its function is yet unclear. The lack of physiological information hinders informed hypotheses. Here, we characterize the synaptic and intrinsic properties of NLOT neurons. We show that the NLOT receives converging olfactory and amygdalar inputs, and that NLOT neurons respond to input with high-rate bursts of action potentials. This suggests that the NLOT, that harbors ∼2500 cells, encodes a low-dimensional signal that is of high importance. We hypothesize that the NLOT assigns emotional value to odors.

Reading reshapes stimulus selectivity in the visual word form area.

Reading depends on a brain region known as the "visual word form area" (VWFA) in left ventral occipito-temporal cortex. This region's function is debated because its stimulus selectivity is not absolute, it is modulated by a variety of task demands, and it is inconsistently localized. We used fMRI to characterize the combination of sensory and cognitive factors that activate word-responsive regions that we precisely localized in 16 adult humans (4 male). We then presented three types of character strings: English words, pseudowords, and unfamiliar characters with matched visual features. Participants performed three different tasks while viewing those stimuli: detecting real words, detecting color in the characters, and detecting color in the fixation mark. There were three primary findings about the VWFA's response: (1) It preferred letter strings over unfamiliar characters even when the stimuli were ignored during the fixation task; (2) Compared to those baseline responses, engaging in the word reading task enhanced the response to words but suppressed the response to unfamiliar characters. (3) Attending to the stimuli to judge their font color had little effect on the response magnitudes. Thus, the VWFA is uniquely modulated by a cognitive signal that is specific to voluntary linguistic processing and is not additive. Functional connectivity analyses revealed that communication between the VWFA and a left frontal language area increased when the participant engaged in the linguistic task. We conclude that the VWFA is inherently selective for familiar orthography, but it falls under control of the language network when the task demands it.Significance Statement The function of the "visual word form area" (VWFA) is controversial. Some researchers emphasize its bottom-up visual selectivity for words, hence the region's common name. Others argue that its activity is explained by feedback from regions that control attention or language. To seek clarity, we investigated what drives the VWFA: seeing words, attending visually to words, or trying to read words. None of those factors was sufficient on its own. Our results support a hybrid model: the VWFA has inherent selectivity for words, but its function is reshaped by voluntary language processing. Thus, with an integrated analysis of sensory inputs, task demands, and network connectivity, we provide some resolution to debates about this important region.

Estrogen receptor beta signaling enhances extinction memory recall for heroin-conditioned cues in a sex- and region-specific manner

Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERβ in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERβ agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERβ across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERβ agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERβ expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERβ’s impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERβ expression across several different brain regions showed that females only had greater expression of ERβ in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERβ agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.

RNA editing regulates glutamatergic synapses in the frontal cortex of a molecular subtype of Amyotrophic Lateral Sclerosis

BackgroundAmyotrophic Lateral Sclerosis (ALS) is a highly heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons, affecting additional cell types and brain regions. Underlying molecular mechanisms are still elusive, in part due to disease heterogeneity. Molecular disease subtyping through integrative analyses including RNA editing profiling is a novel approach for identification of molecular networks involved in pathogenesis.MethodsWe aimed to highlight the role of RNA editing in ALS, focusing on the frontal cortex and the prevalent molecular disease subtype (ALS-Ox), previously determined by transcriptomic profile stratification. We established global RNA editing (editome) and gene expression (transcriptome) profiles in control and ALS-Ox cases, utilizing publicly available RNA-seq data (GSE153960) and an in-house analysis pipeline. Functional annotation and pathway analyses identified molecular processes affected by RNA editing alterations. Pearson correlation analyses assessed RNA editing effects on expression. Similar analyses on additional ALS-Ox and control samples (GSE124439) were performed for verification. Targeted re-sequencing and qRT-PCR analysis targeting CACNA1C, were performed using frontal cortex tissue from ALS and control samples (n = 3 samples/group).ResultsWe identified reduced global RNA editing in the frontal cortex of ALS-Ox cases. Differentially edited transcripts are enriched in synapses, particularly in the glutamatergic synapse pathway. Bioinformatic analyses on additional ALS-Ox and control RNA-seq data verified these findings. We identified increased recoding at the Q621R site in the GRIK2 transcript and determined positive correlations between RNA editing and gene expression alterations in ionotropic receptor subunits GRIA2, GRIA3 and the CACNA1C transcript, which encodes the pore forming subunit of a post-synaptic L-type calcium channel. Experimental data verified RNA editing alterations and editing-expression correlation in CACNA1C, highlighting CACNA1C as a target for further study.ConclusionsWe provide evidence on the involvement of RNA editing in the frontal cortex of an ALS molecular subtype, highlighting a modulatory role mediated though recoding and gene expression regulation on glutamatergic synapse related transcripts. We report RNA editing effects in disease-related transcripts and validated editing alterations in CACNA1C. Our study provides targets for further functional studies that could shed light in underlying disease mechanisms enabling novel therapeutic approaches.

Small non-coding RNA transcriptomic profiling in adult and fetal human brain

Small non-coding RNAs (sncRNAs) make up ~1% of the transcriptome; nevertheless, they play significant roles in regulating cellular processes. Given the complexity of the central nervous system, sncRNAs likely hold particular importance in the human brain. In this study, we provide sncRNA transcriptomic profiles in a range of adult and prenatal brain regions, with a focus on piRNAs, due to their underexplored expression in somatic cells and tissue-specific nature. Using the WIND workflow, which combines two detection methods, we found 1333 (731 miRNAs, 249 piRNAs, 285 snoRNAs, and 68 other sncRNAs) and 1445 unique sncRNAs (770 miRNAs, 307 piRNAs, 289 snoRNAs, and 79 other sncRNAs) in developing and adult brains, respectively. Significant variations were found upon comparison of fetal and adult brain groups, with 82 miRNAs, 17 piRNAs, and 70 snoRNAs enriched in fetal brains and 22 miRNAs, 11 piRNAs in adult brains. This dataset represents a valuable resource for exploring the sncRNA roles in brain function, their involvement in neurological diseases, and the molecular mechanisms behind brain region interactions.

Altered cortico-brainstem connectivity during spontaneous fluctuations in pain intensity in painful trigeminal neuropathy.

Chronic neuropathic pain can result from nervous system injury and can persist in the absence of external stimuli. Although ongoing pain characterizes the disorder, in many individuals, the intensity of this ongoing pain fluctuates dramatically. Previously, it was identified that functional magnetic resonance imaging (fMRI) signal covariations between the midbrain periaqueductal gray matter (PAG), rostral ventromedial medulla (RVM), and spinal trigeminal nucleus (SpV) are associated with moment-to-moment fluctuations in pain intensity in individuals with painful trigeminal neuropathy (PTN). Since this brainstem circuit is modulated by higher brain input, we sought to determine which cortical sites might be influencing this brainstem network during spontaneous fluctuations in pain intensity. Over 12 minutes, we recorded ongoing pain intensity in 24 PTN participants, and classified them as fluctuating (n=13) or stable (n=11). Using a PAG seed, we identified connections between the PAG and emotional-affective sites such as the hippocampal and posterior cingulate cortices, the sensory-discriminative posterior insula, and cognitive-affective sites such as the dorsolateral prefrontal (dlPFC) and subgenual anterior cingulate cortices that were altered dependent on spontaneous high and low pain intensity. Additionally, sliding-window functional connectivity analysis revealed that the dlPFC-PAG connection anticorrelated with perceived pain intensity over the entire 12-minute period. These findings reveal cortical systems underlying moment-to-moment changes in perceived pain in PTN, which likely cause dysregulation in the brainstem circuits previously identified, and consequently alter the appraisal of pain across time.Significance statement Whilst the intensity of an individual's chronic pain is often measured at a specific point in time, it is known that in a large proportion of individuals, pain intensity fluctuates dramatically from moment-to-moment. In individuals with chronic neuropathic pain, we found that these spontaneous pain intensity fluctuations are associated with neural function fluctuations, specifically of function reflected as neural connectivity between brainstem pain modulatory circuits and cortical regions, including the dorsolateral prefrontal and cingulate cortices. These findings raise the possibility that modulating brain regions such as the dorsolateral prefrontal cortex in individuals with fluctuating chronic pain may provide an avenue for analgesic treatment.

Insights into Brominated Flame Retardant Neurotoxicity: Mechanisms of Hippocampal Neural Cell Death and Brain Region-Specific Transcriptomic Shifts in Mice.

Brominated Flame Retardants (BFRs) reduce flammability in a wide range of products including electronics, carpets, and paint, but leach into the environment to result in continuous, population-level exposure. Epidemiology studies have correlated BFR exposure with neurological problems, including alterations in learning and memory. This study investigated the molecular mechanisms mediating BFR-induced cell death in hippocampal cells and clarified the impact of HBCD exposure on gene transcription in the hippocampus, dorsal striatum, and frontal cortex of male mice. Exposure of hippocampus derived HT-22 cells to various flame retardants, including tetrabromobisphenol-A (TBBPA, current use), hexabromocyclododecane (HBCD, phasing out), or 2,2',4,4'-tetrabromodiphenyl ether (BDE-47, phased out) resulted in time, concentration, and chemical-dependent cellular and nuclear morphology alterations, alterations in cell cycle and increases in annexin V staining. All three BFRs increased p53 and p21 expression; however, inhibition of p53 nuclear translocation using pifthrin-α did not decrease cell death. Transcriptomic analysis upon low (10 nM) and cytotoxic (10 μM) BFR exposure indicated that HBCD and BDE-47 altered genes mediating autophagy-related pathways. Further evaluation showed BFR exposure increased LC3-II conversion and autophagosome formation, and co-exposure with the autophagy inhibitor 3-methyladenine (3-MA) attenuated cytotoxicity. Transcriptomic assessment of select brain regions from subchronically HBCD-exposed male mice demonstrated alteration of genes mediating vesicular transport, with greater impact on the frontal cortex and dorsal striatum compared to the dorsal and ventral hippocampus. Immunoblot analysis demonstrated no increases in cell death or autophagy markers, but did demonstrate increases in the SNARE binding complex SNAP29, specifically in the dorsal hippocampus. These data demonstrate that BFRs can induce chemical-dependent autophagy in neural cells in vitro and provide evidence that BFRs induce region-specific transcriptomic and protein expression in the brain suggestive of change in vesicular trafficking.

Iron Chelators and Alzheimer's Disease Clinical Trials.

Alzheimer's disease (AD) is a major neurodegenerative disorder impacting millions of people with cognitive impairment and affecting activities of daily living. The deposition of neurofibrillary tangles of hyperphosphorylated tau proteins and accumulation of amyloid-β (Aβ) are the main pathological characteristics of AD. However, the actual causal process of AD is not yet identified. Oxidative stress occurs prior to amyloid Aβ plaque formation and tau phosphorylation in AD. The role of master antioxidant, glutathione, and metal ions (e.g., iron) in AD are the frontline area of AD research. Iron overload in specific brain regions in AD is associated with the rate of cognitive decline. We have presented the outcome from various interventional trials involving iron chelators intended to minimize the iron overload in AD. To date, however, no significant positive outcomes have been reported using iron chelators in AD and warrant further research.

Association between neural prosody discrimination and language abilities in toddlers: a functional near-infrared spectroscopy study

BackgroundLanguage delay affects near- and long-term social communication and learning in toddlers, and, an increasing number of experts pay attention to it. The development of prosody discrimination is one of the earliest stages of language development in which key skills for later stages are mastered. Therefore, analyzing the relationship between brain discrimination of speech prosody and language abilities may provide an objective basis for the diagnosis and intervention of language delay.MethodsIn this study, all cases(n = 241) were enrolled from a tertiary women’s hospital, from 2021 to 2022. We used functional near-infrared spectroscopy (fNIRS) to assess children’s neural prosody discrimination abilities, and a Chinese communicative development inventory (CCDI) were used to evaluate their language abilities.ResultsNinety-eight full-term and 108 preterm toddlers were included in the final analysis in phase I and II studies, respectively. The total CCDI screening abnormality rate was 9.2% for full-term and 34.3% for preterm toddlers. Full-term toddlers showed prosody discrimination ability in all channels except channel 5, while preterm toddlers showed prosody discrimination ability in channel 6 only. Multifactorial logistic regression analyses showed that prosody discrimination of the right angular gyrus (channel 3) had a statistically significant effect on language delay (odd ratio = 0.301, P < 0.05) in full-term toddlers. Random forest (RF) regression model presented that prosody discrimination reflected by channels and brain regions based on fNIRS data was an important parameter for predicting language delay in preterm toddlers, among which the prosody discrimination reflected by the right angular gyrus (channel 4) was the most important parameter. The area under the model Receiver operating characteristic (ROC) curve was 0.687.ConclusionsNeural prosody discrimination ability is positively associated with language development, assessment of brain prosody discrimination abilities through fNIRS could be used as an objective indicator for early identification of children with language delay in the future clinical application.

Time- and Region-specific Effect of Vortioxetine on Central LPS-induced Transcriptional Regulation of NLRP3 Inflammasome.

Inflammasome overactivation, multiprotein complexes that trigger inflammatory responses, plays a critical role in Major Depressive Disorder (MDD) pathogenesis and treatment responses. Indeed, different antidepressants alleviate depression-related behaviours by specifically counteracting the NLRP3 inflammasome signalling pathway. The immunomodulatory effects of vortioxetine (VTX), a multimodal antidepressant with cognitive benefits, were recently revealed to counter memory impairment induced by a peripheral lipopolysaccharide (LPS) injection 24 hours (h) postchallenge. The potential link between VTX and NLRP3, along with other inflammasomes, remains unexplored. Hence, adult C57BL/6J male mice (n = 73) were fed with a standard or VTX-enriched diet (600 mg/kg of food, 28 days), injected with LPS (830 μg/kg) or saline, and sacrificed 6/24 h post-LPS. At these time-points, transcriptional effects of LPS and VTX's on NLRP3, NLRP1, NLRC4, AIM2 (inflammasomes), ASC and CASP1 (related subunits) and NEK7 mediator (NLRP3 regulator) were assessed in dorsal and ventral hippocampal subregions, frontal-prefrontal cortex and hypothalamus, brain regions serving behavioural-cognitive functions impaired in MDD. Varied expression patterns of inflammasomes were revealed, with long-term NLRP3 and ASC transcriptional changes observed in response to LPS. It was discovered that VTX counteracted the LPS-mediated NLRP3 and ASC upregulation in memory-related brain areas like the dorsal hippocampus at 24 h time-point, potentially via regulating NEK7 expression. No VTX-mediated transcriptional effects were observed on other inflammasomes, reinforcing a potentially specific modulation on the NLRP3 inflammasome signalling pathway. Thus, a novel VTX's molecular mechanism in modulating the NLRP3 inflammasome in a time- and area-specific manner in the brain was highlighted, with significant clinical implications in treating depression and cognitive impairments.</p>.

Transcranial temporal interference stimulation (tTIS) influences event-related alpha activity during mental rotation.

Non-invasive brain stimulation techniques offer therapeutic potential for neurological and psychiatric disorders. However, current methods are often limited in their stimulation depth. The novel transcranial temporal interference stimulation (tTIS) aims to overcome this limitation by non-invasively targeting deeper brain regions. In this study, we aimed to evaluate the efficacy of tTIS in modulating alpha activity during a mental rotation task. The effects of tTIS were compared with transcranial alternating current stimulation (tACS) and a sham control. Participants were randomly assigned to a tTIS, tACS, or sham group. They performed alternating blocks of resting and mental rotation tasks before, during, and after stimulation. During the stimulation blocks, participants received 20 min of stimulation adjusted to their individual alpha frequency (IAF). We assessed shifts in resting state alpha power, event-related desynchronization (ERD) of alpha activity during mental rotation, as well as resulting improvements in behavioral performance. Our results indicate tTIS and tACS to be effective in modulating cortical alpha activity during mental rotation, leading to an increase in ERD from pre- to poststimulation as well as compared to sham stimulation. However, this increase in ERD was not correlated with enhanced mental rotation performance, and resting state alpha power remained unchanged. Our findings underscore the complex nature of tTIS and tACS efficacy, indicating that stimulation effects are more observable during active cognitive tasks, while their impacts are less pronounced on resting neuronal systems.

An Adaptively Weighted Averaging Method for Regional Time Series Extraction of fMRI-based Brain Decoding.

Brain decoding that classifies cognitive states using the functional fluctuations of the brain can provide insightful information for understanding the brain mechanisms of cognitive functions. Among the common procedures of decoding the brain cognitive states with functional magnetic resonance imaging (fMRI), extracting the time series of each brain region after brain parcellation traditionally averages across the voxels within a brain region. This neglects the spatial information among the voxels and the requirement of extracting information for the downstream tasks. In this study, we propose to use a fully connected neural network that is jointly trained with the brain decoder to perform an adaptively weighted average across the voxels within each brain region. We perform extensive evaluations by cognitive state decoding, manifold learning, and interpretability analysis on the Human Connectome Project (HCP) dataset. The performance comparison of the cognitive state decoding presents an accuracy increase of up to 5% and stable accuracy improvement under different time window sizes, resampling sizes, and training data sizes. The results of manifold learning show that our method presents a considerable separability among cognitive states and basically excludes subject-specific information. The interpretability analysis shows that our method can identify reasonable brain regions corresponding to each cognitive state. Our study would aid the improvement of the basic pipeline of fMRI processing.

Hippocampal-prefrontal communication subspaces align with behavioral and network patterns in a spatial memory task.

Rhythmic network states have been theorized to facilitate communication between brain regions, but how these oscillations influence communication subspaces, i.e, the low-dimensional neural activity patterns that mediate inter-regional communication, and in turn how subspaces impact behavior remains unclear. Using a spatial memory task in rats, we simultaneously recorded ensembles from hippocampal CA1 and the prefrontal cortex (PFC) to address this question. We found that task behaviors best aligned with low-dimensional, shared subspaces between these regions, rather than local activity in either region. Critically, both network oscillations and speed modulated the structure and performance of this communication subspace. Contrary to expectations, theta coherence did not better predict CA1-PFC shared activity, while theta power played a more significant role. To understand the communication space, we visualized shared CA1-PFC communication geometry using manifold techniques and found ring-like structures. We hypothesize that these shared activity manifolds are utilized to mediate the task behavior. These findings suggest that memory-guided behaviors are driven by shared CA1-PFC interactions that are dynamically modulated by oscillatory states, offering a novel perspective on the interplay between rhythms and behaviorally relevant neural communication.

Temporal resolution of spike coding in feedforward networks with signal convergence and divergence.

Convergent and divergent structures in the networks that make up biological brains are found universally across many species and brain regions at various scales. Neurons in these networks fire action potentials, or "spikes", whose precise timing is becoming increasingly appreciated as large sources of information about both sensory input and motor output. While previous theories on coding in convergent and divergent networks have largely neglected the role of precise spike timing, our model and analyses place this aspect at the forefront. For a suite of stimuli with different timescales, we demonstrate that structural bottlenecks (small groups of neurons) post-synaptic to network convergence have a stronger preference for spike timing codes than expansion layers created by structural divergence. Additionally, we found that a simple network model with similar convergence and divergence ratios to those found experimentally can reproduce the relative contribution of spike timing information about motor output in the hawkmoth Manduca sexta. Our simulations and analyses suggest a relationship between the level of convergent/divergent structure present in a feedforward network and the loss of stimulus information encoded by its population spike trains as their temporal resolution decreases, which could be confirmed experimentally across diverse neural systems in future studies. We further show that this relationship can be generalized across different models and measures, implying a potentially fundamental link between network structure and coding strategy using spikes.

Lineage-tracing reveals an expanded population of NPY neurons in the inferior colliculus.

Growing evidence suggests that neuropeptide signaling shapes auditory computations. We previously showed that neuropeptide Y (NPY) is expressed in the inferior colliculus (IC) by a population of GABAergic stellate neurons and that NPY regulates the strength of local excitatory circuits in the IC. NPY neurons were initially characterized using the NPY-hrGFP mouse, in which humanized renilla Green Fluorescent Protein (hrGFP) expression indicates NPY expression at the time of assay, i.e., an expression-tracking approach. However, studies in other brain regions have shown that NPY expression can vary based on several factors, suggesting that the NPY-hrGFP mouse might miss NPY neurons not expressing NPY on the experiment date. Here, we hypothesized that neurons with the ability to express NPY represent a larger population of IC GABAergic neurons than previously reported. To test this hypothesis, we used a lineage-tracing approach to irreversibly tag neurons that expressed NPY at any point prior to the experiment date. We then compared the physiological and anatomical features of neurons labeled with this lineage-tracing approach to our prior data set, revealing a larger population of NPY neurons than previously found. In addition, we used optogenetics to test the local connectivity of NPY neurons and found that NPY neurons routinely provide inhibitory synaptic input to other neurons in the ipsilateral IC. Together, our data expand the definition of NPY neurons in the IC, suggest that NPY expression might be dynamically regulated in the IC, and provide functional evidence that NPY neurons form local inhibitory circuits in the IC.

Discovering Neurophysiological Characteristics of Pathological High-Frequency Oscillations in Epilepsy with an Explainable Deep Generative Model.

Interictal high-frequency oscillation (HFO) is a promising biomarker of the epileptogenic zone (EZ). However, objective definitions to distinguish between pathological and physiological HFOs have remained elusive, impeding HFOs' clinical applications. We employed self-supervised deep generative variational autoencoders to learn such discriminative HFO features directly from their morphologies in a data-driven manner. We studied a large retrospective cohort of 185 patients who underwent intracranial monitoring and analyzed 686,410 candidate HFO events collected from 18,265 brain contacts across diverse brain regions. The model automatically clustered HFOs into distinct morphological groups in the latent space. One cluster consisted of putative morphologically defined pathological HFOs (mpHFOs): HFOs in that cluster were observed to be associated with spikes and exhibited high signal intensity both in the HFO band (>80 Hz) at detection and in the sub-HFO band (10-80 Hz) surrounding the detection and were primarily localized in the seizure onset zone (SOZ). Moreover, resection of brain regions based on a higher prevalence of interictal mpHFOs better predicted postoperative seizure outcomes than current clinical standards based on SOZ removal. Our self-supervised, explainable, deep generative model distills pathological HFOs and thus potentially helps delineate the EZ purely from interictal intracranial EEG data.

Hypothalamic and hippocampal transcriptome changes in AppNL-G-F mice as a function of metabolic and inflammatory dysfunction

The progression of Alzheimer’s disease (AD) has a silent phase that predates characteristic cognitive decline and eventually leads to active cognitive deficits. Metabolism, diet, and obesity have been correlated to the development of AD but is poorly understood. The hypothalamus is a brain region that exerts homeostatic control on food intake and metabolism and has been noted to be impacted during the active phase of Alzheimer’s disease. This study, in using an amyloid overexpression AppNL-G-F mouse model under normal metabolic conditions, examines blood markers in young and old male AppNL-G-F mice (n = 5) that corresponds to the silent and active phases of AD, and bulk gene expression changes in the hypothalamus and the hippocampus. The results show a large panel of inflammatory mediators, leptin, and other proteins that may be involved in weakening the blood brain barrier, to be increased in the young AppNL-G-F mice but not in the old AppNL-G-F mice. There were also several differentially expressed genes in both the hypothalamus and the hippocampus in the young AppNL-G-F mice prior to amyloid plaque formation and cognitive decline that persisted in the old AppNL-G-F mice, including GABRa2 receptor, Wdfy1, and several pseudogenes with unknown function. These results suggests that a larger panel of inflammatory mediators may be used as blood markers to detect silent AD, and that a change in leptin and gene expression in the hypothalamus exist prior to cognitive effects, suggesting a coupling of metabolism with amyloid plaque induced cognitive decline.