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Novel stimuli can be stressful for individuals with autism spectrum disorders (ASD), though repeated exposure can reduce this effect. In Cntnap2^-/- and Shank3B^+/- mouse models of ASD, novel background odors impaired behavioral target odor recognition but that deficit improved with training. To investigate the neural basis of this improvement, we used wide-field calcium imaging to measure olfactory bulb responses in Cntnap2^-/- and Shank3B^+/- mice and WT mice of either sex. Training with background odors enhanced both behavioral performance and neural discriminability of odor mixtures in both Cntnap2^-/- and Shank3B^+/- as well as WT mice. Naive Cntnap2^-/- and Shank3B^+/- mice showed greater trial-to-trial neural variability than WT mice, but training stabilized neural responses. Critically, training produced a widespread reduction in olfactory bulb responses to background odors in ASD models, but not in WT mice. Thus, despite similar behavioral improvements as WT mice, Cntnap2^-/- and Shank3B^+/- mice relied on a distinct broad suppression of background odor responses to enhance olfactory coding in the presence of background odors.

Psychedelic drugs have garnered increasing attention for their therapeutic potential in treating a variety of psychiatric diseases, such as depression, anxiety, and substance use disorder. The claustrum (CLA), a brain area with remarkable interconnectivity to frontal cortices, has recently been shown to have a dense population of serotonin 2 receptors (5-HT2Rs) that are activated by psychedelics. Because psychedelic therapy can require as little as one treatment session, it has been speculated that psychedelics achieve their long-term remedial effects by inducing neuroplasticity in brain areas responsible for psychiatric disease states, such as the anterior cingulate cortex (ACC). However, the effects of psychedelics on synaptic plasticity in serotonin receptor-rich brain areas remain entirely unexplored. We applied presynaptic stimuli paired with postsynaptic action potentials (APs) to a subpopulation of CLA neurons projecting to ACC in male rats to find that the psychedelic drug, 2,5-dimethoxy-4-iodoamphetamine (DOI), reverses the polarity of synaptic plasticity from long-term depression (LTD) to long-term potentiation (LTP) in a manner that may reflect contribution of excitatory or inhibitory neurotransmission but is specific to synapses activated by local electrical stimulation. Additionally, we characterize intrinsic electrophysiological properties of CLA-ACC neurons with and without DOI application, noting several changes to AP dynamics induced by DOI. These findings align with the view that psychedelics induce rapid and lasting synaptic plasticity and strengthen the hypothesis that claustrocortical circuits are highly sensitive to psychedelic drug action.

The ability to inhibit and adapt our behavior in response to changing stimuli is a critical component of everyday life. Individuals with Parkinson's disease (PD) may struggle to inhibit behavior, particularly in the presence of dopaminergic therapy, which can result in impulsive behavior. Impulse control disorders are often operationalized in the laboratory using motor inhibition tasks. However, deficits of motor inhibition tasks are not always observed in PD, perhaps because of the nature of the motor inhibition that is engaged in typical tasks (e.g., suppression of incipient movement such as a button press). We employed a novel continuous movement stop task to investigate planned and unplanned motor inhibition during ongoing movement. EEG was recorded during task performance from individuals with PD (OFF and ON dopaminergic medication) and age-matched healthy controls (HC). Participants were of any sex. We found that the time it took for participants to stop a continuous movement was impaired (i.e., longer) in PD patients ON medication compared with both patients OFF medication and HC. This finding was accompanied by diminished midfrontal theta power following the stop signal in PD (ON and OFF) compared with HC. Additionally, an increase in midfrontal beta power was observed, which was higher in unplanned stopping compared with planned for all groups. However, this increase in beta occurred late-after the time of outright stopping. Together, these findings demonstrate that stopping ongoing movements was impaired in PD patients ON medication and theta and beta power play distinct roles in inhibition of movement.

Sleep-wake states bidirectionally interact with epilepsy and seizures, but the mechanisms are unknown. A barrier to comprehensive characterization and the study of mechanisms has been the difficulty of annotating large chronic recording datasets. To overcome this barrier, we sought to develop an automated method of classifying sleep-wake states, seizures, and the postictal state in mice ranging from controls to mice with severe epilepsy with accompanying background electroencephalographic (EEG) abnormalities. We utilized a large dataset of recordings, including electromyogram, EEG, and hippocampal local field potentials, from control and intra-amygdala kainic acid-treated mice. We found that an existing sleep-wake classifier performed poorly, even after retraining. A support vector machine, relying on typically used scoring parameters, also performed below our benchmark. We then trained and evaluated several multilayer neural network architectures and found that a bidirectional long short-term memory-based model performed best. This "Sleep-Wake and Ictal State Classifier" (SWISC) showed high agreement between ground-truth and classifier scores for all sleep and seizure states in an unseen and unlearned epileptic dataset (average agreement 96.41% ± SD 3.80%) and saline animals (97.77 ± 1.40%). Channel dropping showed that SWISC was primarily dependent on hippocampal signals yet still maintained good performance (∼90% agreement) with EEG alone, thereby expanding the classifier's applicability to other epilepsy datasets. SWISC enables the efficient combined scoring of sleep-wake and seizure states in mouse models of epilepsy and healthy controls, facilitating comprehensive and mechanistic studies of sleep-wake and biological rhythms in epilepsy.

Thirst is a strongly motivated internal state that is represented in central brain circuits that are only partially understood. Water seeking is a discrete step of the thirst behavioral sequence that is amenable to uncovering the mechanisms for motivational properties such as goal-oriented behavior, value encoding, and behavioral competition. In Drosophila, water seeking is regulated by the NPY-like neuropeptide NPF; however, the circuitry for NPF-dependent water seeking is unknown. To uncover the downstream circuitry, we identified the NPF receptor NPFR and the neurons it is expressed in as being acutely critical for thirsty water seeking in males. Refinement of the NPFR pattern uncovered a role for a single neuron, the L1-l, in promoting thirsty water seeking. The L1-l neuron increases its activity in thirsty flies and is involved in the regulation of dopaminergic neurons in long-term memory formation. Thus, NPFR and its ligand NPF, already known for its role in feeding behavior, are also important for a second ingestive behavior.

Loss-of-function (LOF) Frazzled/DCC mutants disrupt synaptogenesis in the Giant Fiber (GF) System of Drosophila We observed weaker physiology in LOF male and female specimens, characterized by longer latencies and reduced response frequencies between the GFs and the motor neurons. These physiological phenotypes are linked to a loss of gap junctions in the GFs, specifically the loss of the shaking-B(neural+16) isoform of innexin in the presynaptic terminal. We present evidence of Frazzled's role in gap junction regulation by utilizing the UAS-GAL4 system in Drosophila to rescue mutant phenotypes. Expression of various UAS-Frazzled constructs in a Frazzled LOF background was used to dissect the role of different parts of the Frazzled receptor in the assembly of electrical synapses. Expressing Frazzled's intracellular domain in Frazzled LOF mutants rescued axon pathfinding and synaptogenesis. This is supported by the complementary result that Frazzled fails to rescue synaptic function when the transcriptional activation domain is disrupted, as shown by the deletion of the highly conserved intracellular P3 domain or by a construct with a point mutation in the highly conserved P3 domain known to be required for transcriptional activation. A computational model clarifies the role of gap junctions and the function of the GF System. The present work shows how various domains of a guidance molecule regulate synaptogenesis through the regulation of synaptic components.

Humans rapidly update the control of an ongoing movement following changes in contextual parameters. This involves adjusting the controller to exploit redundancy in the movement goal, such as when reaching for a narrow or wide target, and adapting to dynamic changes such as velocity-dependent force fields (FFs). Although flexible control and motor adaptation are computationally distinct, the fact that both unfold within the same movement suggests that they interact functionally to support task-specific adjustments. To test this hypothesis, we conducted a series of experiments combining changes in the target structure and a force field presented separately or in combination. Seventy-six human participants (both sexes) took part in this study, with each experiment involving different participants. They were asked to reach for a target that could change from a narrow square to a wide rectangle between or during trials. Step loads were used to assess whether participants exploited target redundancy. In a separate experiment, we added a force field in addition to target changes and step loads. Our results revealed a reduced ability to exploit target redundancy when sudden target changes occurred concurrently with FF adaptation. Furthermore, the magnitude of adaptation was reduced when step loads were added to the FF. Crucially, this interference emerged specifically when all perturbations impacted motor execution simultaneously. These results indicate that flexible control and motor adaptation interact in a nontrivial manner, suggesting interdependence between these behavioral mechanisms, and a clear identification of the timescale at which they are engaged-namely, during movement.

This study aims to examine the changes in AQP4 polarity and pericyte vascularity during temporal lobe epilepsy (TLE) progression, with the goal of identifying potential drug targets or strategies to delay the onset and progression of TLE. Chronic TLE was induced in male rats using pilocarpine. AQP4 polarity and pericyte vascular coverage were assessed by immunofluorescence. The effects of modulating AQP4 polarity on PTZ-induced TLE model using male mice were studied. Molecular mechanisms of AQP4 polarity were explored using transwell coculture and transcriptomics, validated at the protein level. ELISA was used to measure PDGF-BB levels in serum and cerebrospinal fluid. Following pilocarpine-induced chronic TLE model establishment, AQP4 polarity and pericyte vascular coverage rapidly increased but later declined, reaching the lowest levels in epileptic animals. Trifluoperazine prevented AQP4 redistribution, reduced seizure duration, and alleviated brain edema in PTZ-induced TLE mouse model. Transcriptomic analysis revealed that pericyte coculture did not alter the expression of dystrophin-associated protein components in astrocytes. Pericyte LAMA1 and LAMA2 levels were significantly higher than endothelial cells, and the levels of pericyte LAMA1 and LAMA2 were significantly increased after coculture with astrocytes. Expression of LAMA1 and LAMA2 around pericytes initially increased and then decreased during chronic TLE progression. PDGF-BB levels decreased over time, reaching the lowest levels during epilepsy. Disrupted AQP4 polarity is closely associated with TLE development. Pericyte vascular coverage appears to influence AQP4 polarity, and key molecules such as laminins and PDGF-BB may help maintain AQP4 polarity, potentially contributing to the attenuation of TLE progression and epileptogenesis.

Aberrant dopamine transmission is a hallmark of several psychiatric disorders. Dopamine neurons in the ventral tegmental area (VTA) display distinct activity states that are regulated by discrete afferent inputs. For example, burst firing requires excitatory input from the mesopontine tegmentum, while dopamine neuron population activity, defined as the number of spontaneously active dopamine neurons, is thought to be dependent on inhibitory drive from the ventral pallidum (VP). Rodent models used to study psychiatric disorders, such as psychosis, consistently exhibit elevated dopamine neuron population activity, due to decreased tonic inhibition from the VP. However, it remains unclear whether the VP can modulate all dopamine neurons or if only a specific subset of VTA dopamine neurons receive innervation from the VP to be recruited as required. This knowledge is critical for understanding dopamine regulation in normal and pathological conditions. Here, we used in vivo electrophysiology in male and female rats to record VTA dopamine neurons inhibited by electrical stimulation of the VP. Specifically, VP stimulation inhibited ∼22% of spontaneously active dopamine neurons; however, activation of the ventral hippocampus, a modulator of VTA population activity, increased the proportion to ∼48%. This increase suggests that VP selectively modulates a subset of dopamine neurons that can be recruited by afferent activation. Anterograde monosynaptic tracing revealed that approximately half of the VTA dopamine neurons receive input from the VP. Taken together, we demonstrate that a subset of VTA dopamine neurons receives monosynaptic input from the VP, providing valuable information regarding the regulation of VTA neuron activity.

Although clinical and experimental evidence highlight the role of the thalamus in voluntary movement production, the involvement of the thalamus in complex motor tasks such as speech production remains to be elucidated. The present study examined neural activity within the bilateral thalamus in 13 participants (seven females) with essential tremor undergoing awake deep brain stimulation implantation surgery, using three speech tasks of varied complexity [vowel vocalization, a diadochokinetic task (DDK), and sentence repetition]. Low-frequency neural activity (delta/theta band) activity was significantly increased during sentence and DDK compared with vowel vocalization in the bilateral motor thalamus and, to a lesser extent, increased for sentence repetition compared with DDK. Moreover, there was prominent prespeech beta band activity, with a greater decrease in the power of beta activity for sentence compared with DDK and vowel vocalization. The greater low-frequency activity in more complex speech tasks may reflect the allocation of additional cognitive resources to monitor the execution of speech motor plans through cortico-thalamo-cortical pathways in a temporally precise manner. The greater decrease in the power of beta activity prior to the onset of sentence repetition may imply greater involvement of the bilateral thalamus in the planning of complex speech tasks. These findings provide new insights into the role of the bilateral thalamus in speech production and may have clinical implications for neurological disorders that affect speech production.