eNeuro最新文献

Reported associations between functional connectivity and affective disorder symptoms are minimally reproducible, which can partially be attributed to difficulty capturing highly variable clinical symptoms in cross-sectional study designs. "Dense sampling" protocols, where participants are sampled across multiple sessions, can overcome this limitation by studying associations between functional connectivity and variable clinical states. Here, we characterized effect sizes for the association between functional connectivity and time-varying positive and negative daily affect in a nonclinical cohort. Data were analyzed from 24 adults who attended four research visits, where participants self-reported daily affect using the PANAS-X questionnaire and completed 39 min of functional magnetic resonance imaging across three passive viewing conditions. We modeled positive and negative daily affect in relation to network-level functional connectivity, with hypotheses regarding within-network connectivity of the default mode, salience/cingulo-opercular, frontoparietal, dorsal attention, and visual networks and between-network connectivity of affective subcortical regions (amygdala and nucleus accumbens) with both default mode and salience/cingulo-opercular networks. Effect sizes for associations between affect and network-level functional connectivity were small and nonsignificant across analyses. We additionally report that functional connectivity variance is largely attributable to individual identity with small relative variance (<3%) accounted for by within-subject daily affect variation. These results support previous reports that functional connectivity is dominated by stable subject-specific connectivity patterns, while additionally suggesting relatively minimal influence of day-to-day affect. Researchers planning studies examining functional connectivity in relation to daily affect, or other varying stable states, should therefore anticipate small effect sizes and carefully consider power in study planning.

The pretectum of vertebrates contains neurons responsive to global visual motion. These signals are sent to the cerebellum, forming a subcortical pathway for processing optic flow. Global motion neurons exhibit selectivity for both direction and speed, but this is usually assessed by first determining direction preference at intermediate velocity (16-32°/s) and then assessing speed tuning at the preferred direction. A consequence of this approach is that it is unknown if and how direction preference changes with speed. We measured directional selectivity in 114 pretectal neurons from 44 zebra finches (Taeniopygia guttata) across spatial and temporal frequencies, corresponding to a speed range of 0.062-1,024°/s. Pretectal neurons were most responsive at 32-64°/s with lower activity as speed increased or decreased. At each speed, we determined if cells were directionally selective, bidirectionally selective, omnidirectionally responsive, or unmodulated. Notably, at 32°/s, 60% of the cells were directionally selective, and 28% were omnidirectionally responsive. In contrast, at 1,024°/s, 20% of the cells were directionally selective, and nearly half of the population was omnidirectionally responsive. Only 15% of the cells were omnidirectionally excited across most speeds. The remaining 85% of the cells had direction tuning that changed with speed. Collectively, these results indicate a shift from a bias for directional tuning at intermediate speeds of global visual motion to a bias for omnidirectional responses at faster speeds. These results suggest a potential role for the pretectum during flight by detecting unexpected drift or potential collisions, depending on the speed of the optic flow signal.

Epilepsy Aphasia Syndrome (EAS) is a spectrum of childhood disorders that exhibit complex co-morbidities that include epilepsy and the emergence of cognitive and language disorders. CNKSR2 is an X-linked gene in which mutations are linked to EAS. We previously demonstrated Cnksr2 knockout (KO) mice model key phenotypes of EAS analogous to those present in clinical patients with mutations in the gene. Cnksr2 KO mice have increased seizures, impaired learning and memory, increased levels of anxiety, and loss of ultrasonic vocalizations (USV). The intricate interplay between these diverse phenotypes at the brain regional and cell type level remains unknown. Here we leverage conditional deletion of the X-linked Cnksr2 in a neuronal cell type manner in male mice to demonstrate that anxiety and impaired USVs track with its loss from excitatory neurons. Finally, we further narrow the essential role of Cnksr2 loss in USV deficits to excitatory neurons of the Anterior Cingulate Cortex (ACC), a region in mice recently implicated in USV production associated with specific emotional states or social contexts, such as mating calls, distress calls, or social bonding signals. Together, our results reveal Cnksr2-based mechanisms that underlie USV impairments that suggest communication impairments can be dissociated from seizures or anxiety. Furthermore, we highlight the cortical circuitry important for initiating USVs.Significance Statement Epilepsy-Aphasia Syndromes are at the severe end of a spectrum of cognitive-behavioral symptoms that are seen in childhood epilepsies and are currently an inadequately understood disorder. The prognosis of EAS is frequently poor and patients have life-long language and cognitive disturbances. We show that the deletion of Cnksr2 specifically within glutamatergic neurons of the anterior cingulate cortex leads to ultrasonic vocalization impairments, providing an important new understanding of the modulation of vocal communication.

The medial frontal cortex (mFC) and locus ceruleus (LC) are two brain areas that have been implicated in a range of cognitive phenomena, such as attention, memory, and decision-making. Regulators of these brain regions at the molecular level are not well understood but might help to elucidate underlying mechanisms of disorders that present with deficits in these cognitive domains. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the prelimbic subregion (PrL) of the mFC and subsequent bulk RNA sequencing from the mouse PrL. We found that stimulation of this circuit caused an increase in transcription of a host of genes, including the Apoe gene. To investigate cell type-specific expression of Apoe in the PrL, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the PrL or a control virus and found that increases in Apoe expression in the PrL following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into how Apoe expression affects function in a cortical microcircuit that is important for attention, memory, and decision-making and point to interneuron-specific expression of Apoe as a potential biomarker for circuit function in disorders such as attention-deficit hyperactivity disorder, schizophrenia, and Alzheimer's disease.

Hydroxychloroquine (HCQ), a well-known antimalarial and anti-inflammatory drug, has demonstrated potential neuroprotective effects in ischemic stroke by inhibiting pyroptosis, a programmed cell death associated with inflammation. This study investigates the impact of HCQ on ischemic stroke pathology using both in vivo and in vitro models. In vivo, C57BL/6 mice subjected to middle cerebral artery occlusion (MCAO) were treated with HCQ. Neurological deficits, infarct volume, and the expression of pyroptosis markers were evaluated. The results demonstrated that HCQ significantly improved motor function and reduced infarct volume in the MCAO mouse model. In vitro, BV2 microglial cells exposed to lipopolysaccharide (LPS) and oxygen-glucose deprivation (OGD) were treated with HCQ. Western blot and immunofluorescence analyses revealed that HCQ effectively suppressed the expression of pyroptosis markers GSDMD and NLRP3 in both in vivo and in vitro models. These findings suggest that HCQ mitigates ischemic stroke damage by inhibiting pyroptosis, highlighting its potential as a therapeutic agent for ischemic stroke. This study provides novel insights into the molecular mechanisms by which HCQ exerts its neuroprotective effects, offering a promising new avenue for developing safe, cost-effective, and widely applicable stroke treatments. The potential of HCQ to modulate neuroinflammatory pathways presents a significant advancement in ischemic stroke therapy, emphasizing the importance of targeting pyroptosis in stroke management and the broader implications for treating neuroinflammatory conditions.Significance Statement Ischemic stroke remains a leading cause of disability and death globally, with limited effective treatments. This study reveals that HCQ significantly mitigates ischemic stroke damage by inhibiting pyroptosis, a form of programmed cell death. Using in vivo and in vitro models, HCQ was shown to improve motor function and reduce infarct volume, highlighting its potential as a neuroprotective agent. These findings offer a promising new therapeutic approach for ischemic stroke, emphasizing the importance of targeting pyroptosis in stroke treatment.

In an effort to increase access to neuroscience education in underserved communities, we created an educational program that utilizes a simple task to measure place preference of the cockroach (Gromphadorhina portentosa) and the open-source free software, SLEAP Estimates Animal Poses (SLEAP) to quantify behavior. Cockroaches (n = 18) were trained to explore a linear track for 2 min while exposed to either air, vapor, or vapor with nicotine from a port on one side of the linear track over 14 d. The time the animal took to reach the port was measured, along with distance traveled, time spent in each zone, and velocity. As characterizing behavior is challenging and inaccessible for nonexperts new to behavioral research, we created an educational program using the machine learning algorithm, SLEAP, and cloud-based (i.e., Google Colab) low-cost platforms for data analysis. We found that SLEAP was within a 0.5% margin of error when compared with manually scoring the data. Cockroaches were found to have an increased aversive response to vapor alone compared with those that only received air. Using SLEAP, we demonstrate that the x-y coordinate data can be further classified into behavior using dimensionality-reducing clustering methods. This suggests that the linear track can be used to examine nicotine preference for the cockroach, and SLEAP can provide a fast, efficient way to analyze animal behavior. Moreover, this educational program is available for free for students to learn a complex machine learning algorithm without expensive hardware to study animal behavior.

Certain structural brain connections have been confirmed to influence sleep duration in children. However, the causal relationships between all brain regions and children's sleep duration remain unclear. A two-sample Mendelian randomization analysis was conducted using data from genome-wide association studies (GWAS) to examine the relationships between 206 structural connections and sleep duration in children. Sensitivity analyses were employed to validate the findings and assess the robustness of the causal inferences. Stronger connectivity from the left hemisphere (LH) control network to the accumbens (β = -0.15; 95% CI = [-0.30, -2.88 × 10^-3]; p = 0.05) and from the LH somatomotor network to the LH default network (β = -0.18; 95% CI = [-0.34, -0.03]; p = 0.02) in white-matter structural connectivity (SC) were associated with shorter sleep durations. Conversely, increased white-matter SC from the LH dorsal attention network to the thalamus (β = 0.14; 95% CI = [8.45 × 10^-4, 0.27]; p = 0.05), from the right hemisphere (RH) control network to the thalamus (β = 0.10; 95% CI = [0.01, 0.19]; p = 0.03), from the RH default network to the thalamus (β = 0.08; 95% CI = [4.53 × 10^-3, 0.16]; p = 0.04), from the RH limbic network to the thalamus (β = 0.15; 95% CI = [0.05, 0.26]; p = 3.77 × 10^-3), and from the RH somatomotor network to the thalamus (β = 0.20; 95% CI = [0.07, 0.32]; p = 1.63 × 10^-3) correlated with longer sleep durations in children. Two-sample Mendelian randomization provides novel insights into the relationships between brain regions and sleep duration in children. Our findings demonstrate a causal relationship between specific brain areas and sleep duration.

Increasing data suggest a crucial relationship between glycolipid metabolic disorder and neuropsychiatric injury. The aim of this study is to investigate the behavioral performance changes and neuropathological injuries in mice challenged with high-fat diet (HFD) and streptozotocin (STZ). The glucose metabolism indicators and behavioral performance were detected. The mRNA expression of IL-1β, IL-6, TNF-α, ocln, zo-1, and clnds and protein expression of APP, p-Tau, p-IRS1, p-AKT, p-ERK, and TREM1/2 were measured. The fluorescence intensities of MAP-2, NeuN, APP, p-Tau, GFAP, and IBA-1 were observed. The results showed that combination of HFD and STZ/I.P. could induce glucose metabolic turmoil and Alzheimer's disease (AD)-like neuropsychiatric dysfunction in mice, as indicated by the increased concentrations of fasting blood glucose and impaired learning and memory ability. Moreover, the model mice presented increased levels of APP, p-Tau, p-IRS1, TREM2, IL-1β, IL-6, TNF-α, ocln, zo-1, and clnds; decreased levels of p-AKT, p-ERK, and TREM1; and neuron damage and the hyperactivation of astrocytes and microglia in the hippocampus as compared with control mice. Only male mice were used in this study. Although AD and type 2 diabetes mellitus (T2DM) are distinct pathologies, our results suggested that combination of HFD and STZ/I.P., a widely used T2DM modeling method, could successfully induce AD-like behavioral impairments and neuropathological injuries in mice; the mechanism might be involved with neuroinflammation and its associated dysfunction of IRS1/AKT/ERK signaling pathway. Our findings further support the potential overlap between T2DM and AD pathophysiology, providing insight into the mechanisms underlying the comorbidity of these diseases.

Autism spectrum disorder (ASD) is characterized by deficits in social interaction and communication, cognitive rigidity, and atypical sensory processing. Recent studies suggest that the basal ganglia, specifically the striatum (NSt), plays an important role in ASD. While striatal interneurons, including cholinergic (ChAT⁺) and parvalbumin-positive (PV⁺) GABAergic neurons, have been described to be altered in animal models of ASD, their specific contribution remains elusive. Here, we combined behavioral, anatomical, and electrophysiological quantifications to explore if interneuron balance could be implicated in atypical sensory processing in cortical and striatal somatosensory regions of rats subjected to a valproic acid (VPA) model of ASD. We found that VPA animals showed a significant decrease in the number of ChAT⁺ and PV⁺ cells in multiple regions (including the sensorimotor region) of the NSt. We also observed significantly different sensory-evoked responses at the single-neuron and population levels in both striatal and cortical regions, as well as corticostriatal interactions. Therefore, selective elimination of striatal PV⁺ neurons only partially recapitulated the effects of VPA, indicating that the mechanisms behind the VPA phenotype are much more complex than the elimination of a particular neural subpopulation. Our results indicate that VPA exposure induced significant histological changes in ChAT⁺ and PV⁺ cells accompanied by atypical sensory-evoked corticostriatal population dynamics that could partially explain the sensory processing differences associated with ASD.

Maintaining concentration on demanding cognitive tasks, such as vigilance (VG) and working memory (WM) tasks, is crucial for successful task completion. Previous research suggests that internal concentration maintenance fluctuates, potentially declining to suboptimal states, which can influence trial-by-trial performance in these tasks. However, the timescale of such alertness maintenance, as indicated by slow changes in pupil diameter, has not been thoroughly investigated. This study explored whether "pupil trends"-which selectively signal suboptimal tonic alertness maintenance at various timescales-negatively correlate with trial-by-trial performance in VG and WM tasks. Using the psychomotor vigilance task (VG) and the visual-spatial two-back task (WM), we found that human pupil trends lasting over 10 s were significantly higher in trials with longer reaction times, indicating poorer performance, compared with shorter reaction time trials, which indicated better performance. The attention network test further validated that these slow trends reflect suboptimal states related to (tonic) alertness maintenance rather than suboptimal performance specific to VG and WM tasks, which is more associated with (phasic) responses to instantaneous interference. These findings highlight the potential role of detecting and compensating for nonoptimal states in VG and WM performance, significantly beyond the 10 s timescale. Additionally, the findings suggest the possibility of estimating human concentration during various visual tasks, even when rapid pupil changes occur due to luminance fluctuations.