Neuroscience
-
Alzheimer's disease (AD), a debilitating neurodegenerative illness, is characterized by neuronal cell loss, mental deficits, and abnormalities in several neurotransmitter and protein systems. AD is also associated with visual disturbances, but their causes remain unidentified. We hypothesize that the visual disturbances stem from retinal changes, particularly changes in the retinal cholinergic system, and that the etiology in the retina parallels the etiology in the rest of the brain. ⋯ We observed that Tg-SwDI mice showed an initial upregulation of AChR gene expression early on (young adults and middle-aged adults), but a downregulation later on (old adults). Furthermore, transgenic animals displayed significant cell loss in the photoreceptor layer and inner retina of the young adult animals, as well as specific cholinergic cell loss, and increased astrocytic gliosis in the middle-aged adult and old adult groups. Our results suggest that the changes observed in AD cerebrum are also present in the retina and may be, at least in part, responsible for the visual deficits associated with the disease.
-
Diabetes mellitus represents a group of metabolic diseases that are characterized by hyperglycemia caused by either lack of insulin production or a reduced ability to respond to insulin. It is estimated that there were 347 million people worldwide who suffered from diabetes in 2008 and incidence is predicted to double by 2050. Neuropathy is the most common complication of long-term diabetes and approximately 30% of these subjects develop chronic neuropathic pain. ⋯ In the current study, we developed chronic and acute insulin-induced neuropathic pain in mice with type 2 insulin-resistant diabetes. Furthermore, we determined that insulin-induced acute allodynia is independent of glycemia levels, can also be induced with Insulin-like Growth Factor 1 (IGF1) and be prevented by inhibition of AKT, providing evidence of an insulin/IGF1 signaling pathway-based mechanism for TIND. This mouse model is useful for the elucidation of mechanisms contributing to TIND and for the testing of new therapeutic approaches to treat TIND.
-
Mutations in the PI3K/Akt/mTOR signaling pathway or in the upstream negative regulator Pten cause human brain overgrowth disorders, such as focal cortical dysplasia and megalencephaly, and are characterized by the presence of hypertrophic neurons. These disorders often have a pediatric onset and a high comorbidity with drug-resistant epilepsy; however, effective pharmacological treatments are lacking. We established forebrain excitatory neuron-specific Pten-deficient cultures as an in vitro model of brain overgrowth disorders, and investigated the effects of this Pten mutation on PI3K/Akt/mTOR signaling and neuronal growth. ⋯ We found that RAD001 treatment only partially reversed the morphological abnormalities of Pten mutant neurons, whereas MK-2206 treatment completely rescued the phenotype. Interestingly, neither treatment altered the size or morphology of normal neurons. Our results suggest that Akt is a major determinant of neuronal growth, and that Akt inhibition may be an effective strategy for pharmacological intervention in brain overgrowth disorders.
-
Major depression is a common cause of chronic disability. Despite decades of efforts, no equivocally accepted animal model is available for studying depression. We tested the validity of a new model based on the three-hit concept of vulnerability and resilience. ⋯ Urocortin1 neurons became over-active in CMVS-exposed PACAP knock out (KO) mice with MD180 history, suggesting the contribution of centrally projecting Edinger-Westphal nucleus to the reduced depression and anxiety level of stressed KO mice. Serotoninergic neurons of the dorsal raphe nucleus lost their adaptation ability to CVMS in MD180 mice. In conclusion, the construct and face validity criteria suggest that MD180 PACAP HZ mice on CD1 background upon CVMS may be used as a reliable model for the three-hit theory.
-
The A5 area at the ventrolateral pons contains noradrenergic neurons connected with other medullary areas involved in the cardiorespiratory control. Its contribution to the cardiorespiratory regulation was previously evidenced in anesthetized conditions. In the present study, we investigated the involvement of the A5 noradrenergic neurons to the basal and chemoreflex control of the sympathetic and respiratory activities in unanesthetized conditions. ⋯ In adult rats, lesions of A5 noradrenergic neurons did not modify the reflex cardiorespiratory adjustments to hypoxia (7% O2) and hypercapnia (7% CO2). In the in situ preparations, the sympatho-excitation, but not the PN reflex response, elicited by either the stimulation of peripheral chemoreceptors (ΔtSN: 110±12% vs 58±8%, P<0.01) or hypercapnia (ΔtSN: 9.5±1.4% vs 3.9±1.7%, P<0.05) was attenuated in A5-lesioned rats compared to controls. Our data demonstrated that A5 noradrenergic neurons are part of the circuitry recruited for the processing of sympathetic response to hypoxia and hypercapnia in unanesthetized conditions.