Circuit compensation is often observed in patients with acute ischemic stroke, suggesting the importance of the interaction between brain regions. Also, contextual fear memory is an association between multisensory contexts and fearful stimuli, for which the interaction between the hippocampus and the amygdala is believed to be critical. To understand how focal ischemia in one region could influence the other region, we used a modified photo-thrombosis to induce focal ischemia in the hippocampus or the amygdala or both in freely-moving rats. We found that the learning curve and short-term memory (STM) were not affected in the rats although focal ischemia was induced 5 h before learning in either the hippocampus or the amygdala; these were impaired by the induction of ischemia in both the regions. Furthermore, the learning curve and STM were impaired when ischemia was induced 24 h before learning in either the hippocampus or the amygdala when the synaptic transmission was altered in one region because of is...

The motor thalamus relays signals from subcortical structures to the motor cortical areas. Previous studies in songbirds and rodents suggest that cortical feedback inputs crucially contribute to the generation of movement-related activity in the motor thalamus. In primates, however, it remains uncertain whether the corticothalamic projections may play a role in shaping neuronal activity in the motor thalamus. Here, using an optogenetic inactivation technique with the viral vector system expressing halorhodopsin, we investigated the role of cortical input in modulating thalamic neuronal activity during goal-directed behavior. In particular, we assessed whether the suppression of signals originating from the supplementary eye field at the corticothalamic terminals could change the task-related neuronal modulation in the oculomotor thalamus in monkeys performing a self-initiated saccade task. We found that many thalamic neurons exhibited changes in their firing rates depending on saccade direction or task eve...

Spontaneous synaptic transmission is regulated by the protein complexin (Cpx). Cpx binds the SNARE complex, a coil-coiled four-helical bundle that mediates the attachment of a synaptic vesicle (SV) to the presynaptic membrane (PM). Cpx is thought to clamp spontaneous fusion events by stabilizing a partially unraveled state of the SNARE bundle; however, the molecular detail of this mechanism is still debated. We combined electrophysiology, molecular modeling, and site-directed mutagenesis in Drosophila to develop and validate the atomic model of the Cpx-mediated clamped state of the SNARE complex. We took advantage of botulinum neurotoxins (BoNTs) B and G, which cleave the SNARE protein synaptobrevin (Syb) at different sites. Monitoring synaptic depression on BoNT loading revealed that the clamped state of the SNARE complex has two or three unraveled helical turns of Syb. Site-directed mutagenesis showed that the Cpx clamping function is predominantly maintained by its accessory helix (AH), while molecular ...

Survival depends on the ability to adaptively react or execute actions based on previous aversive salient experiences. Although lateral habenula (LHb) activity has been broadly implicated in the regulation of aversively motivated responses, it is not clear under which conditions this brain structure is necessary to regulate defensive responses to a threat. To address this issue, we combined pharmacological inactivations with behavioral tasks that involve aversive and appetitive events and evaluated defensive responses in rats. We found that LHb pharmacological inactivation did not affect cued threat conditioning (fear) and extinction (safety) learning and memory, anxiety-like or reward-seeking behaviors. Surprisingly, we found that LHb inactivation abolished reactive defensive responses (tone-elicited freezing) only when threat (conditioning) and safety memories (extinction and latent inhibition) compete during retrieval. Consistently, we found that LHb inactivation impaired active defensive responses [pla...

Past social experience affects the circuitry responsible for producing and interpreting current behaviors. The social behavior network (SBN) is a candidate neural ensemble to investigate the consequences of early-life social isolation. The SBN interprets and produces social behaviors, such as vocalizations, through coordinated patterns of activity (functional connectivity) between its multiple nuclei. However, the SBN is relatively unexplored with respect to murine vocal processing. The serotonergic system is sensitive to past experience and innervates many nodes of the SBN; therefore, we tested whether serotonin signaling interacts with social experience to affect patterns of immediate early gene (IEG; cFos) induction in the male SBN following playback of social vocalizations. Male mice were separated into either social housing of three mice per cage or into isolated housing at 18–24 d postnatal. After 28–30 d in housing treatment, mice were parsed into one of three drug treatment groups: control, fenflur...

Drugs of abuse engage overlapping but distinct molecular and cellular mechanisms to enhance dopamine (DA) signaling in the mesocorticolimbic circuitry. DA neurons of the ventral tegmental area (VTA) are key substrates of drugs of abuse and have been implicated in addiction-related behaviors. Enhanced VTA DA neurotransmission evoked by drugs of abuse can engage inhibitory G-protein-dependent feedback pathways, mediated by GABAB receptors (GABABRs) and D2 DA receptors (D2Rs). Chemogenetic inhibition of VTA DA neurons potently suppressed baseline motor activity, as well as the motor-stimulatory effect of cocaine and morphine, confirming the critical influence of VTA DA neurons and inhibitory G-protein signaling in these neurons on this addiction-related behavior. To resolve the relative influence of GABABR-dependent and D2R-dependent signaling pathways in VTA DA neurons on behavioral sensitivity to drugs of abuse, we developed a neuron-specific viral CRISPR/Cas9 approach to ablate D2R and GABABR in VTA DA neu...

The human auditory system is exceptional at comprehending an individual speaker even in complex acoustic environments. Because the inner ear, or cochlea, possesses an active mechanism that can be controlled by subsequent neural processing centers through descending nerve fibers, it may already contribute to speech processing. The cochlear activity can be assessed by recording otoacoustic emissions (OAEs), but employing these emissions to assess speech processing in the cochlea is obstructed by the complexity of natural speech. Here, we develop a novel methodology to measure OAEs that are related to the time-varying harmonic structure of speech [speech-distortion-product OAEs (DPOAEs)]. We then employ the method to investigate the effect of selective attention on the speech-DPOAEs. We provide tentative evidence that the speech-DPOAEs are larger when the corresponding speech signal is attended than when it is ignored. Our development of speech-DPOAEs opens up a path to further investigations of the contribut...

When performing a long chain of actions in rapid sequence, future movements need to be planned concurrently with ongoing action. However, how far ahead we plan, and whether this ability improves with practice, is currently unknown. Here, we designed an experiment in which healthy volunteers produced sequences of 14 finger presses quickly and accurately on a keyboard in response to numerical stimuli. On every trial, participants were only shown a fixed number of stimuli ahead of the current keypress. The size of this viewing window varied between 1 (next digit revealed with the pressing of the current key) and 14 (full view of the sequence). Participants practiced the task for 5 days, and their performance was continuously assessed on random sequences. Our results indicate that participants used the available visual information to plan multiple actions into the future, but that the planning horizon was limited: receiving information about more than three movements ahead did not result in faster sequence pro...

The impairment of cold-evoked activation of brown adipose tissue (BAT) in rats fed a high-fat diet (HFD) requires the activity of a vagal afferent to the medial nucleus of the solitary tract (mNTS). We determined the role of transient receptor potential vanilloid 1 (TRPV1) activation in the mNTS, and of a dynorphin input to the median preoptic nucleus (MnPO) in the impaired BAT thermogenic response to cold in HFD-fed rats. The levels of some linoleic acid (LA) metabolites, which can act as endogenous TRPV1 agonists, were elevated in the NTS of HFD rats compared with chow-fed rats. In HFD rats, nanoinjections of the TRPV1 antagonist, capsazepine (CPZ) in the NTS rescued the impaired BAT sympathetic nerve activity (BAT SNA) and thermogenic responses to cold. In contrast, in chow-fed rats, cold-evoked BAT SNA and BAT thermogenesis were not changed by nanoinjections of CPZ into the NTS. Axon terminals of NTS neurons that project to the dorsal lateral parabrachial nucleus (LPBd) were closely apposed to LPBd neu...

The reproducibility and translation of neuroscience research is assumed to be undermined by introducing environmental complexity and heterogeneity. Rearing laboratory animals with minimal (if any) environmental stimulation is thought to control for biological variability but may not adequately test the robustness of our animal models. Standard laboratory housing is associated with reduced demonstrations of species typical behaviors and changes in neurophysiology that may impact the translation of research results. Modest increases in environmental enrichment (EE) mitigate against insults used to induce animal models of disease, directly calling into question the translatability of our work. This may in part underlie the disconnect between preclinical and clinical research findings. Enhancing environmental stimulation for our model organisms promotes ethological natural behaviors but may simultaneously increase phenotypic trait variability. To test this assumption, we conducted a systematic review and evalu...