Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid system and the brain's fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3mg/kg) from gestational day (GD) 7 until GD22. Anxiety-like, depressive-like, and reward-seeking behaviour, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted laser...

While recent studies have revealed an involvement of hippocampal interneurons in learning the association among time-separated events, its underlying cellular mechanisms remained not fully clarified. Here, we combined multi-channel recording and optogenetics to elucidate how the hippocampal parvalbumin-expressing interneurons (PV-IN) support associative learning. To address this issue, we trained the mice (box sexes) to learn hippocampus-dependent trace eyeblink conditioning (tEBC) where they associated a light flash conditioned stimulus (CS) with a corneal airpuff unconditioned stimuli (US) separated by a 250-ms time interval. We found that the hippocampal PV-INs exhibited learning-associated sustained activity at the early stage of tEBC acquisition. Moreover, the PV-IN sustained activity was positively correlated with the occurrence of conditioned eyeblink responses at the early learning stage. Suppression of the PV-IN sustained activity impaired the acquisition of tEBC, whereas the PV-IN activity suppre...

Phosphodiesterase (PDE) inhibitors have been safely and effectively used in the clinic and increase the concentration of intracellular cyclic nucleotides (cAMP/cGMP). These molecules activate downstream mediators, including the cAMP-response-element binding (CREB) protein, which controls neuronal excitability and growth responses. CREB gain of function enhances learning, and allocates neurons into memory engrams. CREB was also controls recovery after stroke. PDE-inhibitors are linked to recovery from neural damage and to stroke recovery in specific sites within the brain. PDE2A is enriched in cortex. In the present study, we use a mouse cortical stroke model in young adult and aged male mice to test the effect of PDE2A inhibition on functional recovery, and on downstream mechanisms of axonal sprouting, tissue repair and the functional connectivity of neurons in recovering cortex. Stroke causes deficits in use of the contralateral forelimb, loss of axonal projections in cortex adjacent to the infarct and fu...

It has been suggested that the dorsomedial striatum (DMS) is engaged in the early stages of motor learning for goal-directed actions, whereas at later stages, control is transferred to the dorsolateral striatum (DLS), a process that enables learned motor actions to become a skill or habit. It is not known if these striatal regions are simultaneously active while the expertise is acquired. To address this question, we developed a mouse “treadmill training task” that tracks changes in mouse locomotor coordination during running practice and simultaneously provides a means to measure local neuronal activity using photometry. To measure change in motor coordination over treadmill practice sessions, we used DeepLabCut and custom-built code to analyze body position and paw movements. By evaluating improvements in motor coordination during training with simultaneous neuronal calcium activity in the striatum, we found that DMS direct pathway neurons exhibited decreased activity as the mouse gained proficiency at r...

Parental care is critical for successful reproduction in mammals. Recent work has implicated the hormone prolactin in regulating male parental behavior, similar to its established role in females. Male laboratory mice show a mating-induced suppression of infanticide (normally observed in virgins) and onset of paternal behavior 2 weeks after mating. Using this model, we sought to investigate how prolactin acts in the forebrain to regulate paternal behavior. First, using c-fos immunoreactivity in prolactin receptor (Prlr) Prlr -IRES-Cre-tdtomato reporter mouse sires, we show that the circuitry activated during paternal interactions contains prolactin-responsive neurons in multiple sites, including the medial preoptic nucleus, bed nucleus of the stria terminalis, and medial amygdala. Next, we deleted Prlr from 3 prominent cell types found in these regions: glutamatergic, GABAergic, and CaMKIIα. Prlr-deletion from CaMKIIα, but not glutamatergic or GABAergic cells, had a profound effect on paternal behavior as ...

The human visual system consists of multiple topographic maps that extend from the early visual cortex (EVC) along the dorsal and ventral processing streams. Responses to illusory shapes within these maps have been demonstrated in the ventral stream areas, in particular the lateral occipital complex (LOC). Recently, the intraparietal sulcus (IPS) of the dorsal stream has been linked to the processing of illusory shapes defined by motion. It remains unclear whether the topographically organized parietal areas also respond to stationary illusory shapes, which would suggest their generic role in representing illusory content. In the current study we measured brain responses using fMRI while 30 human participants (12 male) observed flickering inducers around the fixation task. The inducers either formed an illusory diamond in the center, a triangle in the left or right hemifield, or were inverted such that no illusory figure was formed. We compared responses of parietal regions IPS0-IPS5 and SPL1 to each illus...

An increasing number of studies have shown that cross-modal interaction can occur in early sensory cortices. Yet, how neurons in sensory cortices integrate multisensory cues in perceptual tasks and to what extent this influences behavior is largely unclear. To investigate, we examined visual modulation of auditory responses in the primary auditory cortex (A1) in a two-alternative forced-choice task. During the task, male rats were required to make a behavioral choice based on the pure tone frequency (low vs. high) of the self-triggered stimulus to get a water reward. The result showed that the presence of a noninformative visual cue did not uniformly influence auditory response, with frequently enhancing just one of them. Closely correlated with behavioral choice, the visual cue mainly enhanced responsiveness to the auditory cue indicating a movement direction contralateral to A1 recorded. Operating in this fashion afforded A1 neurons a superior capability to discriminate sound during multisensory trials. ...

In vitro and in vivo experimentation in the central nervous system are effective approaches to study its functioning. Manipulations in vitro are characterized by easy experimental control and stable experimental conditions. However, transferring these advantages to in vivo research remains technically and ethically challenging, preventing many research teams from acquiring critical recordings in their animal models. In order to transfer the benefits of in vitro experimentation to in vivo experimentation, we developed a suite of 3d-printed tools (a superfusion chamber with an independent brain presser and animal stand). Using the immature rat barrel cortex as a model, we show that our set of tools (further ’superfusion preparation’) provides stable conditions for electrophysiological and neuroimaging recordings in the neonatal rat neocortex in vivo . Highly correlated intra- and extracellular activity was recorded during spontaneous and evoked cortical activity, supporting the possibility of simultaneous lo...

Thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), regulate growth, metabolism, and neurodevelopment. THs secretion is controlled by the pituitary thyroid-stimulating hormone (TSH) and the hypothalamic-pituitary-thyroid (HPT) axis. The organic anion-transporting polypeptide 1C1 (OATP1C1/Slco1c1) and the monocarboxylate transporter 8 (MCT8/SLC16A2) actively transport THs, which bind to their nuclear receptors and induce gene expression. A mutation in OATP1C1 is associated with brain hypometabolism, gradual neurodegeneration, and impaired cognitive and motor functioning in adolescent patients. In order to understand the role of Oatp1c1 and the mechanisms of the disease, we profiled the transcriptome of oatp1c1 mutant ( oatp1c1-/- ) and mct8-/-xoatp1c1-/- adult male and female zebrafish brains. Among dozens of differentially expressed genes, agouti-related neuropeptide 1 ( agrp1 ) expression increased in oatp1c1-/- adult brains. Imaging in the hypothalamus revealed enhanced proliferation of Agr...

Considerable evidence from mouse models and human postmortem tissue suggests loss of Muscleblind-like protein 2 (MBNL2) function in brain is a major driver of central nervous system symptoms in Myotonic Dystrophy Type 1 (DM1). Increased hypersomnia, fatigue, and surgical complications associated with general anesthesia suggest possible sensitivity to GABAergic inhibition in DM1. To test the hypothesis that MBNL2 depletion leads to behavioral sensitivity to GABAA-R modulation, Mbnl2 KO and WT littermates were treated with the anesthetic sevoflurane, the benzodiazepine diazepam, the imidazopyridine zolpidem, and the benzodiazepine rescue agent, flumazenil (Ro 15-1788), and assessed for various behavioral metrics. Mbnl2 KO mice exhibited delayed recovery following sevoflurane, delayed emergence and recovery from zolpidem, and enhanced sleep time at baseline that was modulated by flumazenil (Ro 15-1788). A significantly higher proportion of Mbnl2 KO mice also loss their righting reflex (LORR) from a standard d...