Sign- versus goal-tracking in rats indicate vulnerability and resistance, respectively, to Pavlovian cue-evoked addictive drug taking and relapse. Here we tested hypotheses predicting that the opponent cognitive-behavioral styles indexed by sign- versus goal tracking include variations in attentional performance which differentially depend on basal forebrain projection systems. Pavlovian Conditioned Approach (PCA) testing was used to identify male and female sign-trackers (STs) and goal-trackers (GTs), as well as rats with an intermediate phenotype (INTs). Upon reaching asymptotic performance in an operant task requiring the detection of visual signals (hits) as well as the reporting of signal absence for 40 min per session, GTs scored more hits than STs, and hit rates across all phenotypes correlated with PCA scores. STs missed relatively more signals than GTs specifically during the last 15 min of a session. Chemogenetic inhibition of the basal forebrain decreased hit rates in GTs but was without effect ...

Navigating through an environment requires knowledge about one’s direction of self-motion (heading) and traveled distance. Behavioral studies showed that human participants can actively reproduce a previously observed travel distance purely based on visual information. Here, we employed EEG to investigate the underlying neural processes. We measured in human observers event-related potentials (ERPs) during visually simulated straight-forward self-motion across a ground plane. The participants’ task was to reproduce (active condition) double the distance of a previously seen self-displacement (passive condition) using a gamepad. We recorded the trajectories of self-motion during the active condition and played it back to the participants in a third set of trials (replay condition). We analyzed EEG activity separately for four electrode clusters: frontal (F), central (C), parietal (P), and occipital (O). When aligned to self-motion on- or offset, response modulation of the ERPs was stronger, and several ERP-...

The oral cavity is exposed to a remarkable range of noxious and innocuous conditions, including temperature fluctuations, mechanical forces, inflammation and environmental and endogenous chemicals. How such changes in the oral environment are sensed is not completely understood. Transient receptor potential (TRP) ion channels are a diverse family of molecular receptors that are activated by chemicals, temperature changes, and tissue damage. In non-neuronal cells, TRP channels play roles in inflammation, tissue development, and maintenance. In somatosensory neurons TRP channels mediate nociception, thermosensation, and chemosensation. To assess whether TRP channels might be involved in environmental sensing in the human oral cavity, we investigated their distribution in human tongue and hard palate biopsies. TRPV3 and TRPV4 were expressed in epithelial cells with inverse expression patterns where they likely contribute to epithelial development and integrity. TRPA1 immunoreactivity was present in fibroblast...

Intraneuronal chloride concentrations ([Cl-]i) decrease during development resulting in a shift from depolarizing to hyperpolarizing γ-aminobutyric acid (GABA) responses via chloride-permeable GABAA receptors. This GABA shift plays a pivotal role in postnatal brain development, and can be strongly influenced by early life experience. Here, we assessed the applicability of the recently developed fluorescent SuperClomeleon (SClm) sensor to examine changes in [Cl-]i using two-photon microscopy in brain slices. We used SClm mice of both sexes to monitor the developmental decrease in neuronal chloride levels in organotypic hippocampal cultures. We could discern a clear reduction in [Cl-]i between DIV3 and DIV9 (equivalent to the second postnatal week in vivo ) and a further decrease in some cells until DIV22. In addition, we assessed alterations in [Cl-]i in the medial prefrontal cortex (mPFC) of P9 male SClm mouse pups after early life stress (ELS). ELS was induced by limiting nesting material between P2 and P...

Alzheimer's Disease (AD) is characterized by the pathological assembly of Aβ peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aβ and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aβ pathologies by knocking the P290S mutation into murine Mapt and crossing these Mapt P290S KI mice with the App NL-G-F KI line. Mapt P290S KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in App NL-G-Fx Mapt P290S KI mice from 18-months of age onwards. Tau pathology was higher in limbic areas, including hippocampus, amygdala and piriform/entorhinal cortex. We also observed AT100- and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by in situ EM. Using a cell-based tau seeding assay, we showed that sarkosyl-insoluble brain extra...

Manipulating the activity of ventral tegmental area dopamine (VTA DA) neurons can drive nocifensive reflexes, and their firing rates are reduced following noxious stimuli. However, the pain-relevant inputs to the VTA remain incompletely understood. In this study, we used male and female mice in combination with identified dopamine and GABA neurons in the VTA that receive excitatory inputs from the periaqueductal grey (PAG), a nexus of ascending pain information. We tested whether PAG-VTA synapses undergo functional plasticity in response to a pain model using optical stimulation in conjunction with slice electrophysiology. We found that acute carrageenan inflammation does not significantly affect the strength of excitatory PAG synapses onto VTA DA neurons. However, at the PAG synapses on VTA GABA neurons, the subunit composition of NMDA receptors is altered; the complement of NR2D subunits at synaptic sites appears to be lost. Thus, our data support a model in which injury initially alters synapses on VTA ...

Coordinating the four limbs is an important feature of terrestrial mammalian locomotion. When the foot dorsum contacts an obstacle, cutaneous mechanoreceptors send afferent signals to the spinal cord to elicit coordinated reflex responses in the four limbs to ensure dynamic balance and forward progression. To determine how the locomotor pattern of all four limbs changes in response to a sensory perturbation evoked by activating cutaneous afferents from one hindlimb, we electrically stimulated the superficial peroneal nerve with a relatively long train at four different phases (mid-stance, stance-to-swing transition, mid-swing, and swing-to-stance transition) of the hindlimb cycle in seven adult cats. The largest functional effects of the stimulation were found at mid-swing and at the stance-to-swing transition with several changes in the ipsilateral hindlimb, such as increased activity in muscles that flex the knee and hip joints, increased joint flexion and toe height, increased stride/step lengths and in...

While the brain has evolved robust mechanisms to counter spatial disorientation, their neural underpinnings remain unknown. To explore these underpinnings, we monitored the activity of anterodorsal thalamic head-direction (HD) cells in rats while they underwent uni- or bi-directional rotation at different speeds and under different conditions (light vs. dark, freely-moving vs. head-fixed). Under conditions that promoted disorientation HD cells did not become quiescent but continued to fire, although their firing was no longer direction-specific. Peak firing rates, burst frequency, and directionality all decreased linearly with rotation speed, consistent with previous experiments where rats were inverted or climbed walls/ceilings in zero-gravity. However, access to visual landmarks spared the stability of preferred firing directions, indicating that visual landmarks provide a stabilizing signal to the HD system while vestibular input likely maintains direction-specific firing. In addition, we found evidence...

Autoantibodies against central nervous system proteins are increasingly being recognized in association with neurological disorders. Although a growing number of neural autoantibodies have been identified, a causal link between specific autoantibodies and disease symptoms remains unclear, as most studies utilize patient derived cerebrospinal fluid (CSF) containing mixtures of autoantibodies. This raises questions concerning mechanism of action and which autoantibodies truly contribute to disease progression. To address this issue, monoclonal autoantibodies were isolated from a young girl with a range of neurological symptoms, some of which reacted with specific GABAA receptor subunits, α1- and α1γ2-subunits, which in this study, we have characterized in detail using a combination of cellular imaging and electrophysiological techniques. These studies in neurons from wild-type mice (C57BL/6J) (RRID:[IMSR_JAX][1]:000664) of mixed-sex revealed that the α1 and α1ɣ2 subunit-specific antibodies have differential ...

Gonadotropin-releasing hormone (GnRH) neurons produce the final output from the brain to control pituitary gonadotropin secretion and thus regulate reproduction. Disruptions to gonadotropin secretion contribute to infertility, including polycystic ovary syndrome (PCOS) and idiopathic hypogonadotropic hypogonadism. PCOS is the leading cause of infertility in women and symptoms resembling PCOS are observed in girls at or near the time of pubertal onset, suggesting that alterations to the system likely occurred by that developmental period. Prenatally androgenized (PNA) female mice recapitulate many of the neuroendocrine phenotypes observed in PCOS, including altered time of puberty, disrupted reproductive cycles, increased circulating levels of testosterone and altered gonadotropin secretion patterns. We tested the hypotheses that the intrinsic properties of GnRH neurons change with puberty and with PNA treatment. Whole-cell current clamp recordings were made from GnRH neurons in brain slices from control an...