Abnormal fear and anxiety can manifest as psychiatric disorders. The bed nucleus of the stria terminalis (BNST) is implicated in sustained responding to, or anticipation of, an aversive event which can be expressed as anticipatory anxiety. The BLA is also active during anticipatory anxiety and sends projections to the BNST. However, little is known about the role for BLA neurons that project to BNST (BLA-BNST) in anticipatory anxiety in rodents. To address this, we tested whether chemogenetic inactivation of the BLA-BNST pathway attenuates sustained conditioned responses produced by anticipation of an aversive stimulus. For comparison, we also assessed BLA-BNST inactivation during social interaction, which is sensitive to unlearned anxiety. We found that BLA-BNST inactivation reduced conditioned sustained freezing and increased social behaviors, but surprisingly, only in males. To determine whether sex differences in BLA-BNST neuronal activity contribute to the differences in behavior, we used in vivo and ...

Calcium imaging using GCaMP indicators and miniature microscopes has been used to image cellular populations during long timescales and in different task phases, as well as to determine neuronal circuit topology and organization. Because the hippocampus (HPC) is essential for tasks of memory, spatial navigation, and learning, calcium imaging of large populations of HPC neurons can provide new insight on cell changes over time during these tasks. All reported HPC in vivo calcium imaging experiments have been done in mouse. However, rats have many behavioral and physiological experimental advantages over mice. In this paper, we present the first (to our knowledge) in vivo calcium imaging from CA1 HPC in freely moving male rats. Using the UCLA Miniscope, we demonstrate that, in rat, hundreds of cells can be visualized and held across weeks. We show that calcium events in these cells are highly correlated with periods of movement, with few calcium events occurring during periods without movement. We additional...

Transactivating response element DNA-binding protein of 43 kDa (TDP-43), which is encoded by the TARDBP gene, is an RNA-binding protein with fundamental RNA processing activities, and its loss-of-function (LOF) has a central role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TARDBP mutations are postulated to inactivate TDP-43 functions, leading to impaired RNA processing. However, it has not been fully examined how mutant TDP-43 affects global RNA regulation, especially in human cell models. Here, we examined global RNA processing in forebrain cortical neurons derived from human induced pluripotent stem cells (iPSCs) with a pathogenic TARDBP mutation encoding the TDP-43K263E protein. In neurons expressing mutant TDP-43, we detected disrupted RNA regulation, including global changes in gene expression, missplicing, and aberrant polyadenylation, all of which were highly similar to those induced by TDP-43 knockdown. This mutation-induced TDP-43 LOF w...

Human multisensory grasping movements (i.e., seeing and feeling a handheld object while grasping it with the contralateral hand) are superior to movements guided by each separate modality. This multisensory advantage might be driven by the integration of vision with either the haptic position only or with both position and size cues. To contrast these two hypotheses, we manipulated visual uncertainty (central vs. peripheral vision) and the availability of haptic cues during multisensory grasping. We showed a multisensory benefit irrespective of the degree of visual uncertainty suggesting that the integration process involved in multisensory grasping can be flexibly modulated by the contribution of each modality. Increasing visual uncertainty revealed the role of the distinct haptic cues. The haptic position cue was sufficient to promote multisensory benefits evidenced by faster actions with smaller grip apertures, whereas the haptic size was fundamental in fine-tuning the grip aperture scaling. These resul...

The posterior parietal cortex (PPC) plays a key role in integrating sensory inputs from different modalities to support adaptive behavior. Neuronal activity in PPC reflects perceptual decision making across behavioral tasks, but the mechanistic involvement of PPC is unclear. In an audiovisual change detection task, we tested the hypothesis that PPC is required to arbitrate between the noisy inputs from the two different modalities and help decide in which modality a sensory change occurred. In trained male mice, we found extensive single-neuron and population-level encoding of task-relevant visual and auditory stimuli, trial history, as well as upcoming behavioral responses. However, despite these rich neural correlates, which would theoretically be sufficient to solve the task, optogenetic inactivation of PPC did not affect visual or auditory performance. Thus, in spite of neural correlates faithfully tracking sensory variables and predicting behavioral responses, PPC was not relevant for audiovisual chan...

Reading words aloud is a fundamental aspect of literacy. The rapid rate at which multiple distributed neural substrates are engaged in this process can only be probed via techniques with high spatiotemporal resolution. We probed this with direct intracranial recordings covering most of the left hemisphere in 46 humans (26 male, 20 female) as they read aloud regular, exception and pseudo-words. We used this to create a spatiotemporal map of word processing and to derive how broadband γ activity varies with multiple word attributes critical to reading speed: lexicality, word frequency, and orthographic neighborhood. We found that lexicality is encoded earliest in mid-fusiform (mFus) cortex, and precentral sulcus, and is represented reliably enough to allow single-trial lexicality decoding. Word frequency is first represented in mFus and later in the inferior frontal gyrus (IFG) and inferior parietal sulcus (IPS), while orthographic neighborhood sensitivity resides solely in IPS. We thus isolate the neural co...

The subthalamic nucleus (STN) has been implicated in motor and non-motor tasks, and is an effective target of deep brain stimulation (DBS) for the treatment of Parkinson's disease, likely in part due to the STN’s projections outside of the basal ganglia to other brain regions. While there is some evidence of a disynaptic connection between the STN and the cerebellum via the pontine nuclei (PN), how the STN modulates the activity of the neurons in the PN remains unknown. Here we addressed this question using a combination of anatomical tracings, optogenetics, and in vivo electrophysiology in both wild-type and transgenic mice of both sexes. Approximately half of recorded neurons in the PN, which were located primarily in the medial area, responded with short latency to both single pulses and trains of optogenetic stimulation of channelrhodopsin (ChR2)-expressing STN axons in awake, head-restrained mice. Furthermore, the increase in the activity of PN neurons correlated with the strength of activation of STN...

Hippocampal place cells form a map of an animal’s environment. Changes in the hippocampal map can be brought about in a number of ways, including changes to the environment, task, internal state of the subject, and the passage of time. These changes in the hippocampal map have been called “remapping”. In this study, we examine remapping during repeated exposure to the same environment. Different animals can have different remapping responses to the same changes. This variability across animals in remapping behavior is not well understood. In this work, we analyzed electrophysiological recordings from the CA3 region of the hippocampus performed by Alme et al. (2014), in which five male rats were exposed to 11 different environments, including a variety of repetitions of those environments. To compare the hippocampal maps between two experiences, we computed average rate map correlation coefficients. We found changes in the hippocampal maps between different sessions in the same environment. These changes co...

Autism spectrum disorder (ASD) is a developmental disorder that is characterized by difficulties with social interaction and interpersonal communication. It has been argued that abnormal attentional function to exogenous stimuli precedes and contributes to the core ASD symptoms. Notably, the locus ceruleus (LC) and its noradrenergic projections throughout the brain modulate attentional function, but the extent to which this locus ceruleus–norepinephrine (LC–NE) system influences attention in individuals with ASD, who frequently exhibit dysregulated alerting and attention orienting, is unknown. We examined dynamic attention control in girls and boys with ASD at rest using the pupil dilation response (PDR) as a noninvasive measure of LC–NE activity. When gender- and age-matched neurotypical participants were passively exposed to an auditory stream, their PDR decreased for recurrent stimuli but remained sensitive to surprising deviant stimuli. In contrast, children with ASD showed less habituation to recurren...

Sensory evidence accumulation is considered a hallmark of decision-making in noisy environments. Integration of sensory inputs has been traditionally studied using passive stimuli, segregating perception from action. Lessons learned from this approach, however, may not generalize to ethological behaviors like navigation, where there is an active interplay between perception and action. We designed a sensory-based sequential decision task in virtual reality in which humans and monkeys navigated to a memorized location by integrating optic flow generated by their own joystick movements. A major challenge in such closed-loop tasks is that subjects’ actions will determine future sensory input, causing ambiguity about whether they rely on sensory input rather than expectations based solely on a learned model of the dynamics. To test whether subjects integrated optic flow over time, we used three independent experimental manipulations: unpredictable optic flow perturbations, which pushed subjects off their traje...