Although cocaine is powerfully rewarding, not all individuals are equally prone to abusing this drug. We postulate that these differences arise in part because some individuals exhibit stronger aversive responses to cocaine that protect them from cocaine seeking. Indeed, using conditioned place preference (CPP) and a runway operant cocaine self-administration task, we demonstrate that avoidance responses to cocaine vary greatly between individual high cocaine-avoider and low cocaine-avoider rats. These behavioral differences correlated with cocaine-induced activation of the rostromedial tegmental nucleus (RMTg), measured using both in vivo firing and c- fos , whereas slice electrophysiological recordings from ventral tegmental area (VTA)-projecting RMTg neurons showed that relative to low avoiders, high avoiders exhibited greater intrinsic excitability, greater transmission via calcium-permeable AMPA receptors (CP-AMPARs), and higher presynaptic glutamate release. In behaving animals, blocking CP-AMPARs in...

The hypothalamic paraventricular nucleus (PVN) controls neuroendocrine axes and the autonomic nervous system to mount responses that cope with the energetic burdens of psychological or physiological stress. Neurons in the PVN that express the angiotensin Type 1a receptor (PVNAgtr1a) are implicated in neuroendocrine and autonomic stress responses; however, the mechanism by which these neurons coordinate activation of neuroendocrine axes with sympathetic outflow remains unknown. Here, we use a multidisciplinary approach to investigate intra-PVN signaling mechanisms that couple the activity of neurons synthesizing corticotropin-releasing-hormone (CRH) to blood pressure. We used the Cre-Lox system in male mice with in vivo optogenetics and cardiovascular recordings to demonstrate that excitation of PVNAgtr1a promotes elevated blood pressure that is dependent on the sympathetic nervous system. Next, neuroanatomical experiments found that PVNAgtr1a synthesize CRH, and intriguingly, fibers originating from PVNAgt...

Human object recognition is dependent on occipito-temporal cortex (OTC), but a complete understanding of the complex functional architecture of this area must account for how it is connected to the wider brain. Converging functional magnetic resonance imaging evidence shows that univariate responses to different categories of information (e.g., faces, bodies, and nonhuman objects) are strongly related to, and potentially shaped by, functional and structural connectivity to the wider brain. However, to date, there have been no systematic attempts to determine how distal connectivity and complex local high-level responses in occipito-temporal cortex (i.e., multivoxel response patterns) are related. Here, we show that distal functional connectivity is related to, and can reliably index, high-level representations for several visual categories (i.e., tools, faces, and places) within occipito-temporal cortex; that is, voxel sets that are strongly connected to distal brain areas show higher pattern discriminabil...

The dorsal region of the bed nucleus of the stria terminalis (dBNST) receives substantial dopaminergic input which overlaps with norepinephrine input implicated in stress responses. Using ex vivo fast scan cyclic voltammetry in male C57BL6 mouse brain slices, we demonstrate that electrically stimulated dBNST catecholamine signals are of substantially lower magnitude and have slower uptake rates compared to caudate signals. Dopamine terminal autoreceptor activation inhibited roughly half of the catecholamine transient, and noradrenergic autoreceptor activation produced an ∼30% inhibition. Dopamine transporter blockade with either cocaine or GBR12909 significantly augmented catecholamine signal duration. We optogenetically targeted dopamine terminals in the dBNST of transgenic (TH:Cre) mice of either sex and, using ex vivo whole-cell electrophysiology, we demonstrate that optically stimulated dopamine release induces slow outward membrane currents and an associated hyperpolarization response in a subset of d...

A successful class of models link decision-making to brain signals by assuming that evidence accumulates to a decision threshold. These evidence accumulation models have identified neuronal activity that appears to reflect sensory evidence and decision variables that drive behavior. More recently, an additional evidence-independent and time-variant signal, named urgency, has been hypothesized to accelerate decisions in the face of insufficient evidence. However, most decision-making paradigms tested with fMRI or EEG in humans have not been designed to disentangle evidence accumulation from urgency. Here we use a face-morphing decision-making task in combination with EEG and a hierarchical Bayesian model to identify neural signals related to sensory and decision variables, and to test the urgency-gating model. 40 females and 34 males took part (mean age 23.4). We find that an evoked potential time-locked to the decision, the centroparietal positivity, reflects the decision variable from the computational mo...

Diverse functions such as decision-making and memory consolidation may depend upon communication between neurons in hippocampus (HP) and prefrontal cortex (PFC). HP replay is a candidate mechanism to facilitate this communication, however details remain largely unknown due to the technical challenges of recording sufficient numbers of HP neurons for replay while also recording PFC neurons. Here we implanted male rats with 40-tetrode drives, split between HP and PFC, during learning of a Y-maze spatial memory task. Surprisingly, we found that in contrast to their non-selectivity for maze arm during movement, a portion of PFC neurons were highly selective for HP replay of different arms. Moreover, PFC neurons' selectivity to HP non-local arm representation during running tended to match their replay arm selectivity and was predictive of future choice. Thus, PFC activity that is tuned to HP activity is best explained by non-local HP position representations rather than HP representation of actual position, pr...

Specific groups have historically been, and continue to be, underrepresented in the biomedical research workforce, especially academia. Career choice is a multi-factorial process that evolves over time; among all trainees, expressed interest in faculty research careers decreases over time in graduate school, but that trend is amplified in women and members of historically underrepresented (UR) racial and ethnic groups (Fuhrmann et al., 2011; Gibbs et al, 2014; Golde & Dore, 2004; Roach & Sauermann, 2017; Sauermann & Roach, 2012). This work was designed to investigate how career interest changes over time among recent neuroscience PhD graduates, and whether differences in career interests are associated with social identity, experiences in graduate school and postdoctoral training, and personal characteristics. We report results from a survey of 1,479 PhD neuroscientists (including 16% underrepresented and 54% women scientists). We saw repeated evidence that individual preferences about careers in general, ...

The entorhinal cortex (EC) is especially vulnerable in the early stages of Alzheimer’s disease (AD). In particular, cognitive deficits have been linked to alterations in the upper layers of EC. In the present report, we examined layers II and III from eight human brain autopsies (four subjects with no recorded neurological alterations and four AD cases). We used stereological methods to assess cortical atrophy of the EC, and possible changes in the volume occupied by different cortical elements (neuronal and glial cell bodies; blood vessels; and neuropil). We performed 3D ultrastructural analyses of synapses using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) to examine possible alterations related to AD. At the light microscope level, we found a significantly lower volume fraction occupied by neuronal bodies in layer III and a higher volume fraction occupied by glial cell bodies in layer II in AD cases. At the ultrastructural level we observed that (i) there was a significantly lower synaptic d...

In macaque monkeys, dorsal intraparietal areas are involved in several daily visuo-motor actions. However, their border and sources of cortical afferents remain loosely defined. Combining retrograde histological tracing and MRI diffusion-based tractography we found a complex hodology of the dorsal bank of the IPS, which can be subdivided into a rostral area PEip, projecting to the spinal cord, and a caudal area MIP lacking such projections. Both include a rostral and a caudal sector, emerging from their ipsilateral, gradient-like connectivity profiles. As tractography estimations, we used the cross-sectional volume of the white matter bundles connecting each area with other parietal and frontal regions, after selecting ROIs corresponding to the injection sites of neural tracers. For most connections, we found a significant correlation between the proportions of cells projecting to all sectors of PEip and MIP along the continuum of the dorsal bank of the IPS and tractography. The latter also revealed “false...

Objective : Dravet syndrome (DS) is a developmental and epileptic encephalopathy with an increased incidence of sudden death. Evidence of interictal breathing deficits in DS suggests that alterations in subcortical projections to brainstem nuclei may exist, which might be driving comorbidities in DS. The aim of this study was to determine if a subcortical structure, the bed nucleus of the stria terminalis (BNST) in the extended amygdala, is activated by seizures, exhibits changes in excitability, and expresses any alterations in neurons projecting to a brainstem nucleus associated with respiration, stress response and homeostasis. Methods : Experiments were conducted using F1 mice generated by breeding 129.Scn1a+/− mice with wildtype C57BL/6J mice. Immunohistochemistry was performed to quantify neuronal c-fos activation in DS mice after observed spontaneous seizures. Whole cell patch clamp and current clamp electrophysiology recordings were conducted to evaluate changes in intrinsic and synaptic excitabil...