Vocal learning species must form and extensively hone associations between sounds and social contingencies. In songbirds, dopamine signaling guides song motor-production, variability, and motivation, but it is unclear how dopamine regulates fundamental auditory associations for learning new sounds. We hypothesized that dopamine regulates learning in the auditory pallium, in part by interacting with local neuroestradiol signaling. Here, we show that zebra finch auditory neurons frequently coexpress D1 receptor (D1R) protein, neuroestradiol-synthase, GABA, and parvalbumin. Auditory classical conditioning increased neuroplasticity gene induction in D1R-positive neurons. In vitro, D1R pharmacological activation reduced the amplitude of GABAergic and glutamatergic currents and increased the latter’s frequency. In vivo , D1R activation reduced the firing of putative interneurons, increased the firing of putative excitatory neurons, and made both neuronal types unable to adapt to novel stimuli. Together, these fi...

The brain is highly sensitive to auditory regularities and exploits the predictable order of sounds in many situations, from parsing complex auditory scenes, to the acquisition of language. To understand the impact of stimulus predictability on perception, it is important to determine how the detection of predictable structure influences processing and attention. Here we use pupillometry to gain insight into the effect of sensory regularity on arousal. Pupillometry is a commonly used measure of salience and processing effort, with more perceptually salient or perceptually demanding stimuli consistently associated with larger pupil diameters. In two experiments we tracked human listeners’ pupil dynamics while they listened to sequences of 50ms tone pips of different frequencies. The order of the tone pips was either random, contained deterministic (fully predictable) regularities (experiment 1, n = 18, 11 female) or had a probabilistic regularity structure (experiment 2, n = 20, 17 female). The sequences w...

Background : About 5 million people die from diseases related to nicotine addiction and tobacco use each year. Nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are important for maintaining drug-use habits. Methods : We examined the notion of re-equilibrating DAergic transmission by inhibiting phosphodiesterase 7 (PDE7), an intracellular enzyme highly expressed in the corticomesolimbic circuitry and responsible for the degradation of cyclic adenosine monophosphate (cAMP), the main second messenger modulated by DA receptor activation. Results: Using selective PDE7 inhibitors, we demonstrated in male rats that systemic PDE7 enzyme inhibition reduced nicotine self-administration and prevented reinstatement to nicotine seeking evoked by cues or by the pharmacological stressor yohimbine. The effect was also observed by direct application of the PDE7 inhibitors into the nucleus accumbens (NAc) shell but not into the cor...

Within the perinatal stroke field, there is a need to establish preclinical models where putative biomarkers for motor function can be examined. In a mouse model of perinatal stroke, we evaluated motor map size and movement latency following optogenetic cortical stimulation against three factors of post-stroke biomarker utility: 1) Correlation to chronic impairment on a behavioral test battery; 2) Amenability to change using a skilled motor training paradigm; 3) Ability to distinguish individuals with potential to respond well to training. Thy1-ChR2-YFP mice received a photothrombotic stroke at postnatal day 7 and were evaluated on a battery of motor tests between days 59-70. Following a cranial window implant, mice underwent longitudinal optogenetic motor mapping both before and after 3 weeks of skilled forelimb training. Map size and movement latency of both hemispheres was positively correlated with impaired spontaneous forelimb use, whereas only ipsilesional hemisphere map size was correlated with perf...

Amacrine cells are interneurons composing the most diverse cell class in the mammalian retina. They help encode visual features such as edges or directed motion by mediating excitatory and inhibitory interactions between input (i.e. bipolar) and output (i.e. ganglion) neurons in the inner plexiform layer (IPL). Like other brain regions, the retina also contains glial cells that contribute to neurotransmitter uptake, metabolic regulation and neurovascular control. Here, we report that in mouse retina (of either sex), an abundant, though previously unstudied inhibitory amacrine cell is coupled directly to Müller glia. Electron microscopic reconstructions of this amacrine type revealed chemical synapses with known retinal cell types and extensive associations with Müller glia, the processes of which often completely ensheathe the neurites of this amacrine cell. Microinjecting small tracer molecules into the somas of these amacrine cells led to selective labelling of nearby Müller glia, leading us to suggest t...

The “habenulopeduncular system” consists of the medial habenula (MHb) and its principal target of innervation, the interpeduncular nucleus (IP). Neurons in the ventral MHb express acetylcholine along with glutamate, and both the MHb and IP are rich in nicotinic acetylcholine receptors. Much of the work on this system has focused on nicotinic mechanisms and their clinical implications for nicotine use, particularly because the IP expresses the α5 nicotinic receptor subunit, encoded by the CHRNA5 gene, which is genetically linked to smoking risk. A working model has emerged in which nicotine use may be determined by the balance of reinforcement mediated in part by nicotine effects on dopamine reward pathways, and an aversive “brake” on nicotine consumption encoded in the MHb-IP pathway. However, recent work has proposed that the IP also receives direct dopaminergic input from the ventral tegmental area (VTA). If correct, this would significantly impact the prevailing model of IP function. Here we have used C...

Chronic vagus nerve stimulation (VNS) has been shown to facilitate learning, but effects of acute VNS on neural coding and behavior remain less well understood. Ferrets implanted with cuff electrodes on the vagus nerve were trained by classical conditioning on an auditory tone frequency-reward association. One tone was associated with reward while another tone was not. Tone frequencies and reward associations were changed every 2 days, requiring learning of a new relationship. When tones were paired with VNS, animals consistently learned the new association within 2 days. When VNS occurred randomly between trials, learning within 2 days was unreliable. In passively listening animals, neural activity in primary auditory cortex and pupil size were recorded before and after acute VNS-tone pairing. After pairing with a neuron’s best-frequency (BF) tone, responses by a subpopulation of neurons were reduced. VNS paired with an off-BF tone or during inter-trial intervals had no effect. The BF-specific reduction i...

Collybistin (CB) is a rho guanine exchange factor found at GABAergic and glycinergic postsynapses that interacts with the inhibitory scaffold protein, gephyrin, and induces accumulation of gephyrin and GABAA receptors (GABAARs) to the postsynapse. We have previously reported that the isoform without the src homology 3 (SH3) domain, CBSH3-, is particularly active in enhancing the GABAergic postsynapse in both cultured hippocampal neurons as well as in cortical pyramidal neurons after chronic in vivo expression in in utero electroporated (IUE) rats. Deficiency of CB in knockout mice results in absence of gephyrin and gephyrin-dependent GABAARs at postsynaptic sites in several brain regions, including hippocampus. In the present study, we have generated an adeno-associated virus (AAV) that expresses CBSH3- in a cre-dependent manner. Using male and female VGLUT1-IRES-cre or VGAT-IRES-cre mice, we explore the effect of overexpression of CBSH3- in hippocampal pyramidal cells or hippocampal interneurons. The resu...

Coordination of skilled movements and motor planning relies on the formation of regionally restricted brain circuits that connect cortex with subcortical areas during embryonic development. Layer 5 neurons that are distributed across most cortical areas innervate the pontine nuclei (basilar pons) by protrusion and extension of collateral branches interstitially along their corticospinal extending axons. Pons-derived chemotropic cues are known to attract extending axons, but molecules that regulate collateral extension to create regionally segregated targeting patterns have not been identified. Here, we discovered that EphA7 and EfnA5 are expressed in the cortex and the basilar pons in a region-specific and mutually exclusive manner, and that their repulsive activities are essential for segregating collateral extensions from corticospinal axonal tracts in mice. Specifically, EphA7 and EfnA5 forward and reverse inhibitory signals direct collateral extension such that EphA7 -positive frontal and occipital cor...

Parkinson's disease (PD) is characterized by progressive dopamine (DA) neuron loss in the SNc. In contrast, DA neurons in the VTA are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the NAc, where the majority of VGLUT2-expressing DA neurons project, exhibit greater resilience compared with DA terminals in the caudate/putamen. More br...