eNeuro最新文献

Food intake is controlled by multiple converging signals: hormonal signals that provide information about energy homeostasis, but also hedonic and motivational aspects of food and food cues that can drive non-homeostatic or "hedonic" feeding. The ventral pallidum (VP) is a brain region implicated in the hedonic and motivational impact of food and foods cues, as well as consumption of rewards. Disinhibition of VP neurons has been shown to generate intense hyperphagia, or overconsumption. While VP gamma-Aminobutyric acidergic (GABA) neurons have been implicated in cue-elicited reward seeking and motivation, the role of these neurons in the hyperphagia resulting from VP activation remains unclear. Here, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to activate VP GABA neurons in non-restricted male and female rats during chow and sucrose consumption. We found that activation of VP GABA neurons increases consumption of chow and sucrose in male rats, but not female rats. Together, these findings suggest that activation of VP GABA neurons can stimulate consumption of routine or highly palatable rewards selectively in male rats.Significance statement The ventral pallidum has been implicated bidirectionally in consumption of both standard food and highly palatable rewards, but the specific neural subpopulations involved have not been identified. Here we chemogenetically excited GABAergic ventral pallidal neurons and tested consumption of standard chow and a sweet sucrose solution. We found that chemogenetic excitation of these neurons stimulated consumption of both rewards but did so specifically in male rats. These results suggest that GABAergic ventral pallidal neurons can drive overconsumption of foods in male rats, but not female rats, raising important questions about the role of ventral pallidum in consumption in females, who have been understudied in this domain.

Selectively stopping individual parts of planned or ongoing movements is an everyday motor skill. For example, while walking in public you may stop yourself from waving at a stranger who you mistook for a friend while continuing to walk. Despite its ubiquity, our ability to selectively stop actions is limited. Canceling one action can delay the execution of other simultaneous actions. This stopping-interference effect on continuing actions during selective stopping may be attributed to a global inhibitory mechanism with widespread effects on the motor system. Previous studies have characterized a transient global reduction in corticomotor excitability by combining brain stimulation with electromyography (EMG). Here, we examined whether global motor inhibition during selective stopping can be measured peripherally and with high temporal resolution using EMG alone. Eighteen participants performed a bimanual anticipatory response inhibition task with their index fingers while maintaining a tonic contraction of the task-irrelevant abductor digiti minimi (ADM) muscles. A time series analysis of the ADM EMG signal revealed transient inhibition during failed stopping compared to go response trials 150 ms to 203 ms following the stop signal. The pattern was observed in both hands during bimanual stop-all trials as well as selective stop-left and stop-right trials of either hand. These results indicate that tonic muscle activity is sensitive to the effects of global motor suppression even when stopping fails. Therefore, EMG can provide a physiological marker of global motor inhibition to probe the time course and extent of stopping processes.Significance Statement The ability to stop ongoing actions is disrupted in a variety of brain disorders, and failing to stop can have dire consequences for personal safety. Successfully stopping an initiated response has a widespread inhibitory effect on motor system excitability. By measuring activity in task-irrelevant muscles during the performance of a stop task we unveiled a novel signature of transient motor system inhibition when stopping fails. The pattern was observed during attempts to selectively and non-selectively stop actions. This temporally precise signature of peripheral inhibition may be leveraged to better examine candidate neural mechanisms, and our non-invasive approach is well-suited for tracking inhibitory control deficits in clinical populations.

Chronic pain is a debilitative disease affecting 1 in 5 adults globally, and is a major risk factor for anxiety (Goldberg and McGee, 2011; Lurie, DI., 2018). Given the current dearth of available treatments for both individuals living with chronic pain and mental illnesses, there is a critical need for research into the molecular mechanisms involved in order to discover novel treatment targets. Cellular homeostasis is crucial for normal bodily functions and investigations of this process may provide better understanding of the mechanisms driving the development of chronic pain. Using the spared nerve injury (SNI) model of neuropathic pain, we found contrasting roles for BECLIN-1 in the development of pain hypersensitivity and anxiety-like behaviors in a sex-dependent manner. Remarkably, we found that male SNI mice with impaired BECLIN-1 function demonstrated heightened mechanical and thermal hypersensitivity compared to male wildtype SNI mice, while female SNI mice with impaired BECLIN-1 function demonstrated similar thresholds to the female wildtype SNI mice. We also found that disruptions of BECLIN-1 prevented SNI induced increases in anxiety-like behaviors in male mice. Our data thus indicate that BECLIN-1 is differentially involved in the nociceptive and emotion components of chronic pain in male but not female mice.Significance Statement One in five adults suffer from chronic pain, and it is a major risk factor for anxiety. Close to three quarters of the population suffering from chronic pain are women, yet the vast majority of pre-clinical research uses solely male models, and excludes females. In this manuscript, we use female and male mice to discover a novel role for BECLIN-1 in neuropathic pain, and comorbid anxiety-like behaviors in mice. We found that disruptions of Beclin-1 reduces nociceptive hypersensitivity whilst preventing pain-induced increases in anxiety-like behaviors. Notably, these effects were sex-dependent, where only males, but not females, showed BECLIN-1 mediated effects. Our data thus indicates that macroautophagy is differentially involved in nociception and anxiety, in male, but not female mice.

Human face categorization has been extensively studied using event-related potentials (ERPs), positing the N170 ERP component as a robust neural marker of face categorization. Recently, the fast periodic visual stimulation (FPVS) approach relying on steady-state visual evoked potentials (SSVEPs) has also been used to investigate face categorization. FPVS studies consistently report strong bilateral SSVEP face categorization responses over the occipito-temporal cortex, with a right hemispheric dominance, closely mirroring the N170 scalp topography. However, it remains unclear whether SSVEP responses can be considered a proxy for the N170 or are driven by different components. To address this question, we recorded electrophysiological signals from observers viewing face and object images during FPVS and ERP paradigms. We quantified the FPVS response in the frequency domain and extracted ERP components, including the P1, N170, and P2, from both the FPVS time domain and ERP paradigms. Our results revealed little relationship between any single ERP component and the FPVS frequency response. Only the peak-to-peak differences between N170 and P2 components consistently explained the FPVS frequency response. Our data show that the FPVS frequency response reflects a later complex neural integration rather than any isolated ERP component, such as the N170. These findings raise important methodological and theoretical considerations regarding the relationship between SSVEPs and transient ERPs. While both markers are indicative of human face categorization, they appear to capture different stages of this cognitive process.Significance Statement Our study untangles the very nature of the electrophysiological neural responses of face categorization. We recorded and directly compared steady-state visual evoked potentials (SSVEPs) with transient event related potentials (ERP) evoked by faces and objects in human observers. Contrary to the assumption associating SSVEPs with the early N170 ERP component, we found that the N170-P2 difference was consistently associated with the SSVEPs. This finding suggests that SSVEPs in fast periodic visual stimulation (FPVS) may reflect later stages of neural processing. Our findings invite to caution when interpreting SSVEP responses, avoiding premature assumptions about their relationship with ERPs. This work highlights the need for integrated research approaches to better understand the complex interplay between SSVEPs and ERPs across different cognitive domains.

High-frequency stimulation (HFS)-induced long-term potentiation (LTP) is generally regarded as a homosynaptic Hebbian-type LTP, where synaptic changes are thought to occur at the synapses that project from the stimulation site and terminate onto the neurons at the recording site. In this study, we first investigated HFS-induced LTP on urethane-anesthetized rats and found that cortical HFS enhances neural responses at the recording site through the strengthening of local connectivity with nearby neurons at the stimulation site, rather than through synaptic strengthening at the recording site. This enhanced local connectivity at the stimulation site leads to increased output propagation, resulting in signal potentiation at the recording site. Additionally, we discovered that HFS can also non-specifically strengthen distant afferent synapses at the HFS site, thereby expanding its impact beyond local neural connections. This form of plasticity exhibits a neo-Hebbian characteristic as it exclusively manifests in the presence of cholecystokinin (CCK) release, induced by HFS. The cortical HFS-induced local LTP was further supported by a behavioral task, providing additional evidence. Our results unveil a previously overlooked mechanism underlying cortical plasticity: synaptic plasticity is more likely to occur around the soma site of strongly activated cortical neurons, rather than solely at their projection terminals.Significance Statement This manuscript reveals that cortical HFS triggers the local release of CCK, a crucial neuromodulator for cortical plasticity, which is released at the HFS site from other cortical efferents rather than in a homosynaptic manner. Therefore, cortical HFS influences long-range cortical efferents through changes at the HFS location, not at the projection terminals. Additionally, the HFS-triggered locally released CCK strengthens long-range afferent synapses to the HFS site. This evidence suggests that a CCK-dependent neo-Hebbian mechanism underlies cortical plasticity.

Mammalian parenting is an unusually demanding commitment. How has the reward system been co-opted to ensure parental care? Previous work has implicated the lateral habenula (LHb), an epithalamic nucleus, as a potential intersection of parenting behavior and reward. Here, we examine the role of the LHb in the maternal behavior of naturally parturient primiparous mouse dams. We show that kainic acid lesions of the LHb induced a severe maternal neglect phenotype in dams toward their biological pups. Next, we demonstrate that chronic chemogenetic inactivation of the LHb using inhibitory DREADDs impaired acquisition and performance of various maternal behaviors, such as pup retrieval and nesting. We present a random intercept model suggesting LHb inactivation prevents the acquisition of pup retrieval, a novel maternal behavior in primiparous mouse dams, and decreases nest building performance, an already-established behavior, in primiparous mouse dams. Lastly, we examine the spatial histology of kainic acid-treated dams with a random intercept model, which suggests the role of LHb in maternal behavior may be preferentially localized at the posterior aspect of this structure. Together, these findings serve to establish the LHb as required for maternal behavior in the mouse dam, thereby complementing previous findings implicating the LHb in parental behavior using pup-sensitized virgin female mice.

It is widely believed that axons in the central nervous system of adult mammals do not regrow following injury. This failure is thought, at least in part, to underlie the limited recovery of function following injury to the brain or spinal cord. Some studies of fixed tissue have suggested that, counter to dogma, norepinephrine (NE) axons regrow following brain injury. Here, we have used in vivo two-photon microscopy in layer 1 of the primary somatosensory cortex in transgenic mice harboring a fluorophore selectively expressed in NE neurons. This protocol allowed us to explore the dynamic nature of NE axons following injury with the selective NE axon toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). Following DSP4, NE axons were massively depleted and then slowly and partially recovered their density over a period of weeks. This regrowth was dominated by new axons entering the imaged volume. There was almost no contribution from local sprouting from spared NE axons. Regrown axons did not appear to use either the paths of previously lesioned NE axons or NE axons that were spared and survived DSP4 as a guide. To measure NE release, GCaMP8s was selectively expressed in neocortical astrocytes and startle-evoked, NE receptor-mediated Ca²⁺ transients were measured. These Ca²⁺ transients were abolished soon after DSP4 lesion but returned to pre-lesion values after 3-5 weeks, roughly coincident with NE axon regrowth, suggesting that the regrown NE axons are competent to release NE in response to a physiological stimulus in the awake mouse.

The relationships between facial expression and color affect human cognition functions such as perception and memory. However, whether these relationships influence selective attention and brain activity contributed to selective attention remains unclear. For example, reddish angry faces increase emotion intensity, but it is unclear whether brain activity and selective attention are similarly enhanced. To investigate these questions, we examined whether event-related potentials for faces vary depending on facial expression and color by recording electroencephalography (EEG) data. We conducted an oddball task using stimuli that combined facial expressions (angry, neutral) and facial colors (original, red, green). The participants counted the number of times a rarely appearing target face stimulus appeared among the standard face stimuli. The results indicated that the difference in P3 amplitudes for the target and standard faces depended on the combinations of facial expressions and facial colors; the P3 for red angry faces were greater than those for red neutral faces. Additionally, facial expression or facial color had no significant main effect or interaction effect on P1 amplitudes for the target, and facial expression had significant main effects only on the N170 amplitude. These findings suggest that the interaction between facial expression and color modulates the P3 associated with selective attention. Moreover, the response enhancement resulting from this interaction appears to occur at a cognitive processing stage that follows the processing stage associated with facial color or expression alone. Our results support the idea that red color increases the human response to anger from an EEG perspective.

The social environment has long been recognized to play an important role in substance use, which is often modeled in rodents using operant conditioning. However, most operant chambers only accommodate one rodent at a time. We present PeerPub-a unique social operant chamber. PeerPub employs touch sensors to track the licking behavior on drinking spouts. When the number of licks meets a set reinforcement schedule, it dispenses a drop of solution with a fixed volume as a reward at the tip of the spout. A radio frequency identification (RFID) chip implanted in each rat's skull identifies it throughout the experiment. The system is managed by a Raspberry Pi computer. We evaluated PeerPub using Sprague Dawley rats in daily 1 h sessions, where supersac (a glucose and saccharin solution) was provided under a fixed-ratio five schedule. We discovered that male rats consumed more supersac in dual rat conditions compared with single rat conditions. These findings illustrate PeerPub's effectiveness in modeling the interaction between motivated behavior and social context. We expect devices like PeerPub will help highlight the role of social environments in substance use disorder phenotypes. All computer code, 3D design, and build instructions for PeerPub can be found at http://github.com/nijie321/PeerPub.

Speech intelligibility declines with age and sensorineural hearing damage (SNHL). However, it remains unclear whether cochlear synaptopathy (CS), a recently discovered form of SNHL, significantly contributes to this issue. CS refers to damaged auditory-nerve synapses that innervate the inner hair cells and there is currently no go-to diagnostic test available. Furthermore, age-related hearing damage can comprise various aspects (e.g., hair cell damage, CS) that each can play a role in impaired sound perception. To explore the link between cochlear damage and speech intelligibility deficits, this study examines the role of CS for word recognition among older listeners. We first validated an envelope-following response (EFR) marker for CS using a Budgerigar model. We then applied this marker in human experiments, while restricting the speech material's frequency content to ensure that both the EFR and the behavioral tasks engaged similar cochlear frequency regions. Following this approach, we identified the relative contribution of hearing sensitivity and CS to speech intelligibility in two age-matched (65-year-old) groups with clinically normal (n=15, 8 females) or impaired audiograms (n=13, 8 females). Compared to a young normal-hearing control group (n = 13, 7 females), the older groups demonstrated lower EFR responses and impaired speech reception thresholds. We conclude that age-related CS reduces supra-threshold temporal envelope coding with subsequent speech coding deficits in noise that cannot be explained based on hearing sensitivity alone.Significance Statement Temporal bone histology reveals that cochlear synaptopathy (CS), characterized by damage to inner hair cell auditory nerve fiber synapses, precedes sensory cell damage and hearing sensitivity decline. Despite this, clinical practice primarily evaluates hearing status based on audiometric thresholds, potentially overlooking a prevalent aspect of sensorineural hearing damage due to aging, noise exposure, or ototoxic drugs-all of which can lead to CS. To address this gap, we employ a novel and sensitive EEG-based marker of CS to investigate its relationship with speech intelligibility. This study addresses a crucial unresolved issue in hearing science: whether CS significantly contributes to degraded speech intelligibility as individuals age. Our study-outcomes are pivotal for identifying the appropriate target for treatments aimed at improving impaired speech perception.