The reward generated by social interactions is critical for promoting prosocial behaviors. Here we present evidence that oxytocin (OXT) release in the ventral tegmental area (VTA), a key node of the brain’s reward circuitry, is necessary to elicit social reward. During social interactions, activity in paraventricular nucleus (PVN) OXTneurons increased. Direct activation of these neurons in the PVN or their terminals in the VTA enhanced prosocial behaviors. Conversely, inhibition of PVN OXTaxon terminals in the VTA decreased social interactions. OXT increased excitatory drive onto reward-specific VTA dopamine (DA) neurons. These results demonstrate that OXTpromotes prosocial behavior through direct effects on VTA DA neurons, thus providing mechanistic insight into how social interactions can generate rewarding experiences.

Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-␤ (A␤) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3␤ (GSK3␤) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3␤. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3␤ through activation of an Akt signaling pathway. Our lead compound Cu II (gtsm) significantly inhibited GSK3␤ in the brains of APP/PS1 transgenic AD model mice. Cu II (gtsm) also decreased the abundance of A␤ trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased A␤ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic A␤ trimers and phosphorylated tau.Alzheimer's disease ͉ bioinorganic chemistry ͉ glycogen synthase kinase ͉ therapeutic ͉ animal model A lzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by impaired cognitive performance and pathologically by cerebral deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Amyloid plaques in AD contain aggregated forms of the 39-to 43-aa amyloid-␤ peptide (A␤) and A␤ is strongly implicated as a causative agent responsible for cognitive failure in AD. A diverse range of mechanisms for A␤ toxicity has been reported (1). A␤ is produced from the amyloid precursor protein (APP) (2-5) and readily aggregates to form insoluble, high-molecular-mass amyloid structures. Intermediates on the A␤ aggregation pathway, primarily low-molecular-mass oligomers such as dimers and trimers, exhibit the greatest neurotoxicity (6-8). In addition to A␤ oligomers, aberrantly phosphor ylated microtubuleassociated protein tau is also associated with cognitive decline in AD (9). Intracellular neurofibrillary tangles in the AD brain contain hyperphosphorylated tau, and A␤ induced cognitive deficits characteristic of AD transgenic mice are attenuated by decreasing levels of endogenous tau (10).It is now widely recognized that a truly effective therapeutic compound for treating AD needs to attenuate both the A␤-and tau-mediated pathologies. Recent positive outcomes for PBT2 in clinical and preclinical trials are therefore pertinent. Lannfelt et al.(11) demonstrated in phase IIa clinical trials that PBT2 lowers plasma A␤ levels and attenuates cognitive decline, and Adlard et al. (12) have shown that PBT2 decreases interstitial A␤ and phosphorylated tau in the brains of AD model mice. PBT2 is a secondgeneration 8-OH quinoline, which, unlike its predecessor clioquinol, lacks iodine and was selected for clinical development because of its easier chemical synthesis, higher solubility, and increased blood-brain barrier perme...

Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and

The PET imaging agent CuII(atsm) improves motor and cognitive function in Parkinson’s disease.

Background:Cu II (atsm) [(diacetylbis(N(4)-methylthiosemicarbazonato) copper(II)] was orally administrated to transgenic SOD1 G93A mice. Results: Treatment significantly prolonged lifespan with preservation of motor neurons. Reduced protein oxidation, attenuated astrocyte, and microglial activation also resulted from treatment. Conclusion:Cu II (atsm) is neuroprotective in this model even when treatment begins after the onset of disease symptoms. Significance: The drug has therapeutic potential for amyotrophic lateral sclerosis.

Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.

Identification of neural circuit changes contributing to behavioral plasticity has routinely been conducted on candidates that were preselected based on past results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles. Using rabies virus monosynaptic tracing we mapped cocaine-induced global input changes onto ventral tegmental area (VTA) neurons. Cocaine increased rabies labeled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus previously not known to participate in behavioral plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labeling. Inhibition of GPe activity revealed its vital role in two different forms of cocaine-triggered behavioral plasticity, at least in part via GPe-mediated disinhibition of VTA dopamine neuron activity. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioral adaptations.

Alzheimer's disease is an age-related neurodegenerative disorder with its toxicity linked to the generation of amyloid-␤ peptide (A␤). Within the A␤ sequence, there is a systemic repeat of a GxxxG motif, which theoretical studies have suggested may be involved in both peptide aggregation and membrane perturbation, processes that have been implicated in A␤ toxicity. We synthesized modified A␤ peptides, substituting glycine for leucine residues within the GxxxG repeat motif (GSL peptides). These GSL peptides undergo ␤-sheet and fibril formation at an increased rate compared with wild-type A␤. The accelerated rate of amyloid fibril formation resulted in a decrease in the presence of small soluble oligomers such as dimeric and trimeric forms of A␤ in solution, as detected by mass spectrometry. This reduction in the presence of small soluble oligomers resulted in reduced binding to lipid membranes and attenuated toxicity for the GSL peptides. The potential role that dimer and trimer species binding to lipid plays in A␤ toxicity was further highlighted when it was observed that annexin V, a protein that inhibits A␤ toxicity, specifically inhibited A␤ dimers from binding to lipid membranes.