Network analyses inform complex systems such as human brain connectivity, but this approach is seldom applied to gold-standard histopathology. Here, we use two complimentary computational approaches to model microscopic progression of the main subtypes of tauopathy versus TDP-43 proteinopathy in the human brain. Digital histopathology measures were obtained in up to 13 gray matter (GM) and adjacent white matter (WM) cortical brain regions sampled from 53 tauopathy and 66 TDP-43 proteinopathy autopsy patients. First, we constructed a weighted non-directed graph for each group, where nodes are defined as GM and WM regions sampled and edges in the graph are weighted using the group-level Pearson's correlation coefficient for each pairwise node comparison. Additionally, we performed mediation analyses to test mediation effects of WM pathology between anterior frontotemporal and posterior parietal GM nodes. We find greater correlation (i.e., edges) between GM and WM node pairs in tauopathies compared with TDP-4...

Type 1 vanilloid receptors (VR1) have been identified recently in the brain, in which they serve as yet primarily undetermined purposes. The endocannabinoid anandamide (AEA) and some of its oxidative metabolites are ligands for VR1, and AEA has been shown to afford protection against ouabain-induced in vivo excitotoxicity, in a manner that is only in part dependent on the type 1 cannabinoid (CB1) receptor. In the present study, we assessed whether VR1 is involved in neuroprotection by AEA and by arvanil, a hydrolysis-stable AEA analog that is a ligand for both VR1 and CB1. Furthermore, we assessed the putative involvement of lipoxygenase metabolites of AEA in conveying neuroprotection. Using HPLC and gas chromatography/mass spectroscopy, we demonstrated that rat brain and blood cells converted AEA into 12-hydroxy- N -arachidoylethanolamine (12-HAEA) and 15-hydroxy- N -arachidonoylethanolamine (15-HAEA) and that this conversion was blocked by addition of the lipoxygenase inhibitor nordihydroguaiaretic acid....

CBP (CREB-bind protein) was originally characterized as a transcriptional coactivator of CREB (cAMP response element-binding protein). CREB has been implicated in many forms of synaptic plasticity and shown to be critical for memory consolidation. Mutations of CBP were found in the human genetic disease Rubinstein-Taybi Syndrome (RTS) that is characterized by skeletal abnormalities and mental retardation. To date, the function of CBP in the adult central nervous system has not been clearified yet. Mouse lines with CBP mutations were generated using the Cre/loxP system. A deletion of exon 2 in the CREB-binding domain (CBD) results in a frame shift and, thus, to a truncated CBP protein (CBPstop523). Three mouse lines were obtained: CBD2.floxed, which can be crossed with Cre-expressing mouse lines to obtain tissue-specific CBP mutations; CBD2.floxed.neo, which might represent a hypomorphic allele due to the presence of the Neo cassette; and the conventional CBP knock-out (CBD allele). Fear conditioning tests ...

Dopamine (DA) neurons in the ventral tegmental area have been implicated in psychiatric disorders and drug abuse. Understanding the mechanisms through which their activity is regulated via the modulation of afferent input is imperative to understanding their roles in these conditions. Here we demonstrate that endocannabinoids liberated from DA neurons activate cannabinoid CB1 receptors located on glutamatergic axons and on GABAergic terminals targeting GABAB receptors located on these cells. Endocannabinoid release was initiated by inhibiting either presynaptic type-III metabotropic glutamate receptors or postsynaptic calcium-activated potassium channels, two conditions that also promote enhanced DA neuron excitability and bursting. Thus, activity-dependent release of endocannabinoids may act as a regulatory feedback mechanism to inhibit synaptic inputs in response to DA neuron bursting, thereby regulating firing patterns that may fine-tune DA release from afferent terminals.

Cocaine dependence is a complex neuropsychiatric disorder manifested as dysregulation of multiple behavioral, emotional, and cognitive constructs. Neuroimaging studies have begun to identify specific neurobiological circuit impairments in cocaine-dependent (CD) individuals that may underlie these symptoms. However, whether, where, and how the interactions within and between these circuits are disrupted remain largely unknown. We used resting-state fMRI and modularity network analysis to identify brain modules of a priori interest (default-mode network [DMN], salience network [SN], executive control network [ECN], medial temporal lobe [MTL], and striatum) in 47 CD and 47 matched healthy control (HC) participants and explored alterations within and between these brain modules as a function of addiction. At the module level, intermodule connectivity decreased between DMN and SN in CD. At the nodal level, several regions showed decreased connections with multiple modules in CD: the rostral anterior cingulate c...

Acute cannabinoid exposure causes profound stimulation or inhibition of the hypothalamic-pituitary-adrenal or -gonadal axes, respectively. However, the neural mechanism(s) by which cannabinoids elicit their neuroendocrine effects is/are not clear. In the current study, levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in specific brain areas involved in neuroendocrine regulation in the female rat to examine the potential role of 5-HT in cannabinoid effects. Adult female rats were ovariectomized and, four weeks later, implanted with jugular cannulae 24 hr prior to treatment with either iv delta-9-tetrahydrocannabinol (THC; 0.5 mg/kg), HU-210 (0.02 mg/kg) or vehicle control. At 15, 60 or 120 min post-treatment, trunk blood was collected for hormone analyses and selected brain tissues were dissected and rapidly frozen prior to HPLC analysis for 5-HT and 5-HIAA. Plasma levels of ACTH and corticosterone were significantly increased by 15 min and remained increased at 120 min post-...

There is evidence that cannabis use is associated with an increased incidence of schizophrenia1 which raises the possibility that abnormalities in the cannabinoid system could be involved in the pathology of the illness. To begin to address this question we used in situ radioligand binding and autoradiography to measure [3H]CP 55,940 binding to the cannabinoid1 (CB1) receptor in the frontal cortex (FC), caudate-putamen (CP) and temporal lobe (TL) from 14 schizophrenic subjects and 14 non-schizophrenic subjects. To delineate between cannabis receptors [3H]CP 55,940 was displaced by 10μM SR 141716A, a CB1 receptor antagonist. Five schizophrenic subjects and 4 non-schizophrenic subjects had a history of cannabis use confirmed by the presence of plasma THC. The remaining subjects had no history of cannabis use and no plasma THC. Analysis of [3H]CP 55,940 using two way ANOVA showed that there was an increase in the density of radioligand binding in the FC from subjects with schizophrenia compared to that in non...

Cannabinoids, the active constituents of marijuana, are known to impair learning and memory. Receptors for cannabinoids are highly expressed in the hippocampus, a brain region that is believed to play an important role in certain forms of learning and memory. To investigate the possible contribution of cannabinoid receptor-mediated deficits in hippocampal function to the learning and memory impairments produced by marijuana, we studied the effects of cannabinoid receptor activation on two models of learning and memory, long-term potentiation (LTP) and long-term depression (LTD), in hippocampal slices. Although LTP and LTD of CA1 field potentials were blocked by cannabinoid receptor activation in the presence of Mg2+, they could be induced after Mg2+ was removed. Similarly, LTP and LTD of whole-cell EPSCs were unimpaired in the presence of cannabinoid receptor agonist when the postsynaptic membrane was depolarized during the LTP or LTD induction protocol. Cannabinoid receptor activation also reduced EPSCs a...

While humans and other mammals exhibit adaptation to odorants, the neural mechanisms and brain locations involved in this process are incompletely understood. One possibility is that it primarily occurs as a result of the interactions between odorants and odorant receptors on the olfactory sensory neurons in the olfactory epithelium. In this scenario, adaptation would arise as a peripheral phenomenon transmitted to the brain. An alternative possibility is that adaptation occurs because of processing in the brain. We made an initial test of these possibilities using a two-color imaging strategy to simultaneously measure the activity of the olfactory receptor nerve terminals (input to the bulb) and mitral/tufted cell apical dendrites (output from the bulb) in anesthetized and awake mice. Repeated odor stimulation at the same concentration resulted in a decline in the bulb output, while the input remained relatively stable. Thus, the mammalian olfactory bulb appears to participate in generating the perception...

Increasing evidence suggests that cannabis exposure during neurodevelopment (i.e., perinatal, adolescent ages) results in persistent alterations in brain circuits underlying neuropsychiatric disorders and leads to an increased risk for certain psychiatr...