We investigated the effect of transient dopamine depletion on functional connectivity during performance of the Wisconsin Card Sorting Task. Functional magnetic resonance imaging data were analyzed as a psychophysiological interaction, a statistical method used to identify functional connectivity during experimental manipulations. Nineteen healthy subjects were scanned, double blind, on 2 separate days: once after drinking an amino acid mixture deficient in the dopamine precursors tyrosine and phenylalanine, and once after drinking a nutritionally balanced mixture. In the balanced drink session, statistically significant connectivity between the frontal lobes and striatum was observed during set shifting, and the greater the prefrontostriatal connectivity, the faster the response time after a shift. Neither of these associations were observed after dopamine depletion. Moreover, dopamine depletion also reduced the degree of deactivation in areas normally suppressed during attention-demanding tasks, includin...

Primary cilia are essential for CNS development. In the mouse, they play a critical role in patterning the spinal cord and telencephalon via the regulation of Hedgehog/Gli signaling. However, despite the frequent disruption of this signaling pathway in human forebrain malformations, the role of primary cilia in forebrain morphogenesis has been little investigated outside the telencephalon. Here we studied development of the diencephalon, hypothalamus and eyes in mutant mice in which the Ftm/Rpgrip1l ciliopathy gene is disrupted. At the end of gestation, Ftm −/− fetuses displayed anophthalmia, a reduction of the ventral hypothalamus and a disorganization of diencephalic nuclei and axonal tracts. In Ftm −/− embryos, we found that the ventral forebrain structures and the rostral thalamus were missing. Optic vesicles formed but lacked the optic cups. In Ftm −/− embryos, Sonic hedgehog ( Shh ) expression was virtually lost in the ventral forebrain but maintained in the zona limitans intrathalamica (ZLI), the mi...

Deletion of cannabinoid CB1 receptors or SR141716A-induced blockade of CB1 receptors abolishes or significantly attenuates THC, heroin, ethanol, nicotine, but not cocaine self-administration or conditioned place preference, suggesting that CB1 receptor antagonists could be promising in treatment of drug addiction (Le Foll and Goldberg, 2005). It was also reported that SR141716A dose-dependently inhibits cocaine- or cocaine-associated cue-triggered reinstatement of drug-seeking behavior (De Vries et al., 2001). In the present study, we examined whether the novel CB1 receptor antagonist AM 251, which is more potent and selective than SR141716A for CB1 receptors, attenuates cocaine-induced enhancement of brain stimulation reward and cocaine self-administration under a progressive-ratio reinforcement schedule. We found that pretreatment with AM 251 (0.3, 1, 3 mg/kg, i.p., 30 min prior to cocaine) dose-dependently attenuates (74, 65, 96%, respectively) 2 mg/kg cocaine-induced enhancement of brain stimulation re...

The transcription factor ΔFosB accumulates and persists in brain in response to chronic stimulation. This accumulation after chronic exposure to drugs of abuse has been demonstrated previously by Western blot in several brain regions, including the nucleus accumbens, dorsal striatum, amygdala, and frontal cortex. In the present study, we used immunohistochemistry to define with greater anatomical precision the induction of ΔFosB after chronic drug treatment. We used two antibodies; one that recognizes both FosB and ΔFosB, and another that recognizes FosB only. Animals received one of five chronic drug treatments or the respective control: cocaine, self-administered cocaine, morphine, Δ9-THC, or ethanol. Each drug treatment increased the number of ΔFosB immunoreactive cells in a region-specific manner in brain. All treatments induced ΔFosB in the nucleus accumbens, although some differences were seen. For example, ΔFosB induction occurred in both the core and shell after cocaine and the other treatments, bu...

CNS responses to cannabis are mediated by the G protein-coupled CB1 receptor. CB1 is known to couple preferentially to Gi/Go G proteins, inhibiting calcium channels, among other actions. Here we used calcium photometry to monitor the effect of CB1 activation on intracellular calcium concentration. Local perfusion with 5 micromolar of the CB1 aminoalkylindole (AAI) agonist, WIN55,212-2 (WIN), increased intracellular calcium by several hundred nM in HEK293 cells stably expressing CB1 receptors and in cultured hippocampal neurons. The calcium increase was blocked by co-incubation with the CB1 receptor antagonist, SR141716A, and was absent in non-transfected HEK293 cells as well as in hippocampal neurons cultured from CB1 knockout mice. The calcium rise was WIN-specific, being absent in cells treated with other classes of cannabinoid agonists including delta-9-tetrahydrocannabinol and HU210 (classical cannabinoids), CP55,940 (a non-classical cannabinoid) and methanandamide (an eicosanoid cannabinoid) and the n...

In Alzheimer’s disease (AD), tau is aberrantly processed, forming insoluble aggregates that are deposited in the form of neurofibrillary tangles. Phosphorylation at multiple sites, cleavage of the tau protein, and altered conformational states have been cited as possible avenues to tangle formation. Specifically, we have shown that cleavage at Asp421 by caspase enhances polymerization and is associated with increased apoptosis in neuronal cultures. In aging and AD, cleaved tau is evident in NFT, dystrophic neurites and neuropil threads. In vivo, tau appears to be phosphorylated at Ser422 prior to its cleavage; in vitro, this phosphorylation can slow caspase cleavage and inhibit polymerization of tau. In this study, we use immunohistochemistry to examine the presence of phospho-Ser422 and the Asp421 cleavage epitope in non-AD tauopathies including Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). We show that Asp421-cleaved tau, which is prevalent in AD, is als...

Marijuana and endogenous cannabinoids affect brain function primarily by activating the G-protein-coupled cannabionoid receptor-1 (CB1). In the neocortex, CB1 receptors are selectively expressed by a subset of GABAergic interneurons. It has been proposed that these cells regulate rhythmic activity and play a key role in mediating cannabinoid cognitive actions. The physiology, anatomy and synaptic connectivity of neocortical CB1-expressing (CB1+) interneurons remain, however, poorly studied. Electrical coupling among other classes of cortical interneurons have been recently shown to contribute to the generation of rhythmic synchronous activity. It is therefore important to establish whether CB1+ interneurons are also interconnected via electrical synapses. We addressed these issues using paired-recordings in acute slices of mouse neocortex and identified a population of CB1+ interneurons in layer II/III. These cells were multipolar or bitufted in appearance with a widely extending axon, and exhibited a char...

Parkinson’s disease (PD) is a chronic neurodegenerative disease, of unknown etiology, causing progressive loss of nigrostriatal dopamine (DA) neurons and disabling motor impairments. Current therapeutic interventions are aimed at alleviating PD symptoms but fail to halt the underlying progressive degeneration of DA neurons. Thus, there is an urgent need to acquire more information on the pathogenesis of PD to develop alternative therapeutic strategies. Cannabinoid receptors – the pharmacological target of marijuana – are highly expressed in brain regions implicated in PD. In addition, cannabinoid drugs have been shown to be neuroprotective in several in vitro and in vivo models of neurotoxicity. However, no information is available as to whether cannabinoid drugs protect nigrostriatal DA neurons from neurotoxicity induced by MPTP – a neurotoxin that has been extensively used to model PD in animals. We found that CB1 receptors are present in both striatum and substantia nigra pars compacta of the intact C57...

Many studies have shown that the active components of marijuana (cannabinoids) may exhibit neuroprotective properties. Both exogenous and endogenous cannabinoids bind to CB1 receptors found in several areas of the brain, including the cerebellum and hippocampus. Our study investigated the potential neuroprotective properties of cannabinoids on the spastic Han Wistar rat (sHW). Neurodegeneration in the cerebellum and hippocampus cause the sHW rat to exhibit hyperactivity, fore limb tremor, and hind limbs ataxia, leading to death at 65 days. To examine changes in CB1 receptor expression in the sHW rats, slices from mutant and normal siblings were processed for immunohistochemistry. At 30 days of age, there were no staining differences between the mutant and normal rats in any sections. In 60 day mutant hippocampus sections, an increase in CB1 expression was seen in the striatum oriens, indicating possible reorganization of the hippocampus. In 60 day mutant cerebellar sections, despite substantial Purkinje ce...

Resting state functional connectivity MRI (rs-fcMRI) may provide a powerful and noninvasive “bridge” for comparing brain function between patients and experimental animal models; however, the relationship between human and macaque rs-fcMRI remains poorly understood. Here, using a novel surface deformation process for species comparisons in the same anatomical space ([Van Essen, 2004][1], [2005][2]), we found high correspondence, but also unique hub topology, between human and macaque functional connectomes. The global functional connectivity match between species was moderate to strong ( r = 0.41) and increased when considering the top 15% strongest connections ( r = 0.54). Analysis of the match between functional connectivity and the underlying anatomical connectivity, derived from a previous retrograde tracer study done in macaques ([Markov et al., 2012][3]), showed impressive structure–function correspondence in both the macaque and human. When examining the strongest structural connections, we found a ...