Neuroscience
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Damage to the cholinergic input to the prefrontal cortex has been implicated in neuropsychiatric disorders. Cholinergic endings release acetylcholine, which activates nicotinic and/or G-protein-coupled muscarinic receptors. Muscarinic receptors activate transduction systems, which control cellular effectors that regulate the membrane potential in medial prefrontal cortex (mPFC) neurons. ⋯ CCh-dependent depolarization was abolished in the presence of antibodies against Nav1.9 channels in the intracellular solution and augmented by the presence of ProTx-I toxin (100 nM) in the extracellular solution. CCh-induced depolarization was not affected by the following reagents: intracellular transduction system blockers, including U-73122 (10 μM), chelerythrine chloride (5 μM), SQ 22536 (100 μM) and H-89 (2 μM); channel blockers, including Ba(++) ions (200 μM), apamin (100 nM), flufenamic acid (200 μM), 2-APB (200 μM), SKF 96365 (50 μM), and ZD 7288 (50 μM); and a Na(+)/Ca(++) exchanger blocker, benzamil (20 μM). We conclude that muscarinic M1 receptor-dependent depolarization in mPFC pyramidal neurons is evoked by the activation of Nav1.9 channels and that the signal transduction pathway involves G-protein βγ subunits.
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Constraints involving the delivery method of glial cell line-derived neurotrophic factor (GDNF) have hampered its efficacy as a neuroprotectant in Parkinson's disease. Ex vivo gene therapy, in which suitable cells, such as bone marrow-derived mesenchymal stem cells (MSCs), are genetically engineered to overexpress GDNF (GDNF-MSCs) prior to transplantation may be more beneficial than direct brain infusion of the neurotrophin. Previously, GDNF-MSCs have been assessed in the commonly employed 6-hydroxydopamine neurotoxic model of Parkinson's disease. ⋯ Following transplantation of GDNF-MSCs to the striatum, dense areas of TH-positive staining directly proximal to the transplant site were observed. Most importantly, this effect was observed only in the GDNF-MSC transplanted group and not the GFP-MSC transplanted group demonstrating protection and/or sprouting of the dopaminergic terminals induced by the secreted GDNF. This study is the first to highlight the neurotrophic capability of GDNF in the inflammation-driven LPS model and, while future studies will endeavor to improve this approach by increasing cell survival, this work highlights the potential of GDNF delivery by ex vivo gene therapy using MSCs.
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Maternal diabetes during pregnancy may increase the risk of neurodevelopmental disorders in the offspring by increasing inflammation. A major source of inflammatory signaling observed in diabetes is activation of the receptor for advanced glycation end-products (RAGE), and increased RAGE expression has been reported in psychiatric disorders. Thus, we sought to examine whether maternal diabetes creates a proinflammatory state, triggered largely by RAGE signaling, that alters normal brain development and behavior of the offspring. ⋯ In an operant-based strategy set-shifting task, STZ offspring did not differ from controls on an initial visual discrimination or reversal learning but took significantly longer to shift to a new strategy (i.e., set-shift). Insulin replacement with an implantable pellet in the dams reversed the effects of maternal diabetes on RAGE expression, hippocampal excitability, prepulse inhibition and object-place memory, but not anxiety-like behavior or set-shifting. Taken together, these results suggest that chronic maternal hyperglycemia alters normal hippocampal development and behavior of the offspring, effects that may be mediated by increased RAGE signaling in the fetal brain.
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Schizophrenia is a devastating mental illness. Although its etiology is still largely unknown, strides have been taken throughout the last several decades to elucidate the nature of the neuropathology behind this disorder. The advent of neuroimaging technologies such as computerized axial tomography and magnetic resonance imaging have progressed knowledge about the macroscopic brain changes that occur in schizophrenia, including the characteristic enlarged ventricle size and reductions in gray matter volume, whole-brain volume, and white matter anisotropy. ⋯ This is consistent with neuroimaging data and implicates an altered aging trajectory as a factor in the pathogenesis of schizophrenia. Combined with evidence from other neuroanatomical studies reviewed here, as well as studies in childhood-onset schizophrenia, the evidence converges on a progressive neurodevelopmental model of schizophrenia related to altered neuroplasticity. The evidence also supports a particular vulnerability of inhibitory cortical circuits with markers of interneurons showing some of the more consistent reductions in schizophrenia.
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Adult attachment style (AAS) is a personality trait that affects social cognition. Behavioral data suggest that AAS influences mentalizing proficiency, i.e. the ability to predict and explain people's behavior with reference to mental states, but the neural correlates are unknown. We here tested how the AAS dimensions "avoidance" (AV) and "anxiety" (ANX) modulate neural correlates of mentalizing. ⋯ Our task elicited a strong activation of the mentalizing network, including bilateral precuneus, (anterior, middle, and posterior) cingulate cortices, temporal poles, inferior frontal gyri (IFG), temporoparietal junctions, superior medial frontal gyri as well as right medial orbital frontal gyrus, superior temporal gyrus, middle frontal gyrus (MFG), and amygdala. We found that AV is positively and ANX negatively correlated with task-associated neural activity in the right amygdala, MFG, midcingulate cortex, and superior parietal lobule, and in bilateral IFG. These data suggest that avoidantly attached adults activate brain areas implicated in emotion regulation and cognitive control to a larger extent than anxiously attached individuals during mentalizing.