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...

Mice are opportunistic omnivores that readily learn to hunt and eat insects such as crickets. The details of how mice learn these behaviors and how these behaviors may differ in strains with altered neuroplasticity are unclear. We quantified the behavior of juvenile wild type and Shank3 knockout mice as they learned to hunt crickets during the critical period for ocular dominance plasticity. This stage involves heightened cortical plasticity including homeostatic synaptic scaling, which requires Shank3, a glutamatergic synaptic protein that, when mutated, produces Phelan-McDermid syndrome and is often comorbid with autism spectrum disorder (ASD). Both strains showed interest in examining live and dead crickets and learned to hunt. Shank 3 knockout mice took longer to become proficient, and, after 5 days, did not achieve the efficiency of wild type mice in either time-to-capture or distance-to-capture. Shank3 knockout mice also exhibited different characteristics when pursuing crickets that could not be exp...

Recent experimental work on zebrafish has shown the in-vivo activity of photoreceptors and horizontal cells(HCs) as a function of the stimulus spectrum, highlighting the appearance of chromatic-opponent signals at their first synaptic connection. Altogether with the observed lack of excitatory inter-cone connections, these findings suggest that the mechanism yielding early color-opponency in zebrafish is dominated by inhibitory feedback. We propose a neuronal population model based on zebrafish retinal circuitry to investigate whether networks with predominantly inhibitory feedback are more advantageous in encoding chromatic information than networks with mixed excitatory and inhibitory mechanisms. We show that networks with dominant inhibitory feedback exhibit a unique and reliable encoding of chromatic information. In contrast, this property is not guaranteed in networks with strong excitatory inter-cone connections, exhibiting bistability. These findings provide a theoretical explanation for the absence...

The importance of action-perception loops necessitates efficient computations linking motor and sensory systems. Corollary discharge (CD), a concept in motor-to-sensory transformation, has been proposed to predict the sensory consequences of actions for efficient motor and cognitive control. The predictive computation has been assumed to realize via inhibiting sensory reafference when actions are executed. Continuous control throughout the course of action demands inhibitory function ubiquitously on all potential reafference when sensory consequences are not available prior to execution. However, the temporal and functional characteristics of CD are unclear – When does CD begin to operate? To what extent does CD inhibit sensory processes? How is the inhibitory function implemented in neural computation? Using a delayed articulation paradigm with three types of auditory probes (speech, non-speech, and non-human sounds) in an electroencephalography (EEG) experiment with 20 human participants (7 male), we fou...

Pavlovian fear conditioning is a prevalent tool in the study of aversive learning, which is a key component of stress-related psychiatric disorders. Adult rats can exhibit various threat-related behaviors, including freezing, motor responses and ultrasonic vocalizations (USVs). While these responses can all signal aversion, we know little about how they relate to one another. Here we characterize USVs emitted by male and female rats during cued fear acquisition and extinction and assess the relationship between different threat-related behaviors. We found that males consistently emitted more 22 kHz calls (referred to here as “alarm calls”) than females, and that alarm call frequency in males, but not females, related to the intensity of the shock stimulus. Interestingly, 25% of males and 45% of females did not emit any alarm calls at all. Males that did make alarm calls had significantly higher levels of freezing than males who did not, while no differences in freezing were observed between female alarm ca...

Glucocorticoid signaling influences hippocampal-dependent behavior and vulnerability to stress-related neuropsychiatric disorders. In mice, lifelong overexpression of glucocorticoid receptor (GR) in forebrain excitatory neurons altered exploratory behavior, cognition, and dorsal hippocampal gene expression in adulthood, but whether GR overexpression alters the information encoded by hippocampal neurons is not known. We performed in vivo microendoscopic calcium imaging of 1359 dorsal CA1 pyramidal cells in freely behaving male and female WT and GR-overexpressing (GRov) mice during exploration of a novel open field, where most CA1 neurons are expected to respond to center location and mobility. Most neurons showed sensitivity to center location and/or mobility based on single-neuron calcium amplitude and event rate, but these sensitivity patterns differed between genotypes. GRov neurons were more likely than WT neurons to display center sensitivity and less likely to display mobility sensitivity. More than o...