Neuroscience
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Brain glucose metabolism is altered in sporadic Alzheimer's disease (sAD), whose pathologies are reproduced in rodents by intracerebroventricular (icv) infusion of streptozotocin (STZ) in subdiabetogenic doses. The icv-STZ model also culminates in central cholinergic dysfunctions, which in turn are known to underlie both the sAD cognitive decline, and synaptic plasticity impairments. Considering the cognitive-enhancing potential of chronic nicotine (Nic), we investigated whether it attenuates icv-STZ-induced impairments in recognition memory and synaptic plasticity in a cognition-relevant substrate: the hippocampal CA1-medial prefrontal cortex (mPFC) pathway. ⋯ We found that Nic treatment prevents icv-STZ-induced disruptions in recognition memory and LTP. STZ did not precipitate neuronal death, while Nic alone was associated with higher neuronal density in CA1 when compared to vehicle-injected animals. Through combining behavioral, neurophysiological, and neuropathological observations into the Nic-STZ interplay, our study reinforces that cholinergic treatments are of clinical importance against early-stage Alzheimer's disease and mild cognitive impairments.
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The molecular sensor of innocuous (painless) cold sensation is well-established to be transient receptor potential cation channel, subfamily M, member 8 (TRPM8). However, the role of transient receptor potential cation channel, subfamily A, member 1 (TRPA1) in noxious (painful) cold sensation has been controversial. We find that TRPA1 channels contribute to the noxious cold sensitivity of mouse somatosensory neurons, independent of TRPM8 channels, and that TRPA1-expressing neurons are largely non-overlapping with TRPM8-expressing neurons in mouse dorsal-root ganglia (DRG). ⋯ The combination of these two factors, combined with the relatively weak agonist-like activity of cold temperature on TRPA1 channels, partially explains why few TRPA1-expressing neurons respond to cold. Blocking KV channels also reveals another subclass of noxious cold-sensitive DRG neurons that do not express TRPM8 or TRPA1 channels. Altogether, the results of this study provide novel insights into the cold-sensitivity of different subclasses of somatosensory neurons.
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Numerous clinical and experimental observations suggest that deficient neuronal signaling in the globus pallidus externa (GPe) is integral to both Parkinson's disease (PD) and dystonia. In our previous studies in jaundiced dystonic rats, widespread silencing of neurons in GP (rodent equivalent to GPe) preceded and persisted during dystonic motor activity. We therefore hypothesized that on a background of slow and highly irregular and bursty neuronal activity in GP, cortical motor drive produces profound inhibition of GP as the basis for action-induced dystonia in Gunn rats. ⋯ Next, we compared the deep brain stimulation contact sites in the GP internus used to treat patients with PD (n=21 implants in 12 successive patients) versus dystonia (n=16 implants in nine patients) and found the efficacious territory for ameliorating PD to be located chiefly dorsal to that for dystonia. The comparative distribution for treating PD versus dystonia was therefore anatomically consistent with that for inducing these features via GP lesions in rodents. Our collective findings thus suggest that dystonia and parkinsonism are differentially produced by pathological silencing of GPe neurons along distinct motor sub-circuits, resulting in disparate pathological basal ganglia output signaling.
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The group II metabotropic glutamate receptors mGluR2 and mGluR3 are key modulators of glutamatergic neurotransmission. In order to identify novel Group II metabotropic glutamate receptor (mGluR)-interacting partners, we screened the C-termini of mGluR2 and mGluR3 for interactions with an array of PDZ domains. These screens identified the Na+/H+ exchanger regulatory factors 1 and 2 (NHERF-1 & -2) as candidate interacting partners. ⋯ Electron microscopic analyses revealed that Group II mGluRs were primarily expressed in glia and unmyelinated axons in WT, NHERF-1 and NHERF-2 KO mice, but the relative proportion of labeled axons over glial processes was higher in NHERF-2 KO mice than in controls and NHERF-1 KO mice. Interestingly, our anatomical studies also revealed that loss of either NHERF protein results in ventriculomegaly, which may be related to the high incidence of hydrocephaly that has previously been observed in NHERF-1 KO mice. Together, these studies support a role for NHERF-1 and NHERF-2 in regulating the distribution of Group II mGluRs in the murine brain, while conversely the effects of the mGluR2/3 PDZ-binding motifs on receptor signaling are likely mediated by interactions with other PDZ scaffold proteins beyond the NHERF proteins.
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Immune activation (IA) during the early neonatal period is a risk factor for the development of schizophrenia. Lipopolysaccharide (LPS) injected in neonates lead to behavioral and brain changes that persist to adult life. We investigated oxidative stress, levels of cytokines, and the locomotor activity of IA in a schizophrenia animal model in which neonatal male Wistar rats were administered with an injection of LPS (50μg/kg) on postnatal day 3 and different doses of ketamine (5, 15 and 25mg/kg) for 7days during adulthood. ⋯ Catalase in the PFC and hippocampus was reduced in the LPS- and saline-induced in the ketamine (25mg/kg)-treated animals. Pro- and anti-inflammatory cytokines were lower in the brains of LPS-induced in the higher dose ketamine-treated rats. IA influences the locomotor activity and cytokine levels induced by ketamine, and it has a negative effect in potentiating the oxidative stress by higher doses of ketamine in the brain.