Neuroscience
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Human acidic fibroblast growth factor (haFGF), a neurotrophin-like growth factor in the brain, plays important roles in the development, differentiation and regeneration of brain neurons, which makes it potential to treat Alzheimer's disease (AD). In this study, haFGF(14-154) and TAT-haFGF(14-154) (haFGF(14-154) fused with the cell-penetrating peptide transactivator of transcription protein transduction domain (TAT-PTD)) were intranasally administrated for 5 weeks to investigate the effects on senescence-accelerated mouse prone-8 (SAMP8) mice (a mouse model of AD). Results showed that TAT-PTD could increase the concentration of haFGF in the brain significantly, and TAT-haFGF(14-154) was more effective than haFGF(14-154) in the same dosage (300 μg/kg). ⋯ TAT-haFGF(14-154) also significantly reduced β-amyloid protein(1-42) (Aβ(1-42)) deposits as well as the levels of Aβ soluble forms in the mice brains and prevented the neurons from apoptosis. Besides, the oxidative stress impairment in the brain and serum was also ameliorated. The results suggest that TAT-haFGF(14-154) could attenuate the disease progression of SAMP8 AD mice, and the mechanism is related to the regulation of neurons microenvironment including neurotransmitters, Aβ pathology and oxidative stress.
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Several studies in rodents have shown that dysfunctions of the thalamic reticular nucleus (TRN) result in deficits of sensory gating and attentional processes, two core features of schizophrenia. TRN receives inputs from the prefrontal cortex (PFC) and hippocampal formation, two structures which send excitatory projections to the nucleus accumbens (NAcc) and are interconnected with the basolateral amygdala (BLA). Here we determined whether (and which) changes occurred four weeks after a TRN lesion in the dendritic morphology of pyramidal neurons of layers 3 and 5 of the PFC, neurons of ventral and dorsal hippocampus, BLA, and the medium spiny neurons of the NAcc. ⋯ We also evaluated the effects of TRN lesion on exploratory behavior assessed by hole-board test and locomotor activity induced by a novel environment. We found that TRN damage induced a reduction in the exploratory behavior measured by hole-board test with neuronal hypotrophy in PFC (layer 5), CA1 ventral hippocampus and NAcc neurons. Taken together, these data suggest that the behavioral and morphological effects of TRN lesion are, at least partially, mediated by limbic subregions with possible consequences for schizophrenia-related behaviors.
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Alzheimer's disease (AD) is the most prevalent form of dementia affecting the elderly. Evidence has emerged signifying that stimulation of the reelin pathway should promote neural plasticity and suppress molecular changes associated with AD, suggesting a potential therapeutic application to the disease. ⋯ F-spondin overexpression also suppressed endogenous levels of amyloid beta (Aβ(42)) in these mice and reduced Aβ plaque deposition while improving synaptophysin expression in transgenic mouse models of AD. These data demonstrate pathologic and cognitive improvements in mice through F-spondin overexpression.
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Synaptic plasticity is a crucial step in the development of central sensitization in the pathogenesis of neuropathic hyperalgesia. Menin, the product of the multiple endocrine neoplasia type 1 (MEN1) gene, possesses the property of synaptogenesis which plays an essential role in neuronal activity. We tested the contributing role of spinal menin in peripheral nerve injury-induced neuropathic hypersensitivity through modulating neuronal synaptic plasticity. ⋯ Intrathecal ASO alleviated nerve injury-induced mechanical and thermal hypersensitivity. Upregulated spinal menin after nerve injury colocalized with NeuN in the superficial laminae; genetic knockdown of spinal menin reduced nerve injury induced in vivo spontaneous activity and instantaneous frequency and in vitro field potentials; ASO decreased the frequency and amplitude of monosynaptic EPSCs, and reduced synaptic strength and total charge. Collectively, these findings highlight the role of upregulated neuronal menin in the spinal cord in potentiating spinal synaptic plasticity in peripheral nerve injury-induced neuropathic hypersensitivity.
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Mitochondrial dysfunction has been implicated in several psychiatric disorders, including depression. Given that the B-cell-lymphoma 2 (Bcl-2) protein family plays a role in the regulation of mitochondrial apoptotic pathway, we hypothesized that ratio of proapoptotic to antiapoptotic proteins (e.g., Bcl-2-associated X protein (Bax)/Bcl-2) may determine prosurvival/proapoptotic intracellular signaling under stress. We tested this hypothesis by examining the effects of 2h of acute stress immobilization (IM) or cold (C), 21days of social isolation as chronic stress and combined stress (chronic stress followed by acute stress) on cytosolic/mitochondrial levels and ratios of Bax and Bcl-2 proteins in relation to cytosolic nitric oxide (NO) metabolites (nitrates and nitrites) and p53 protein redistribution between cytosolic and mitochondrial compartments in the prefrontal cortex (PFC) and hippocampus (HIPP) of male Wistar rats. ⋯ Translocation of p53 and proapoptotic Bax from the cytosol into mitochondria in response to NO overproduction following combined stressors was detected only in the PFC. These data indicate that chronic isolation stress exerts opposing actions on p53 and NO mechanisms in a tissue-specific manner (PFC vs. HIPP), triggering proapoptotic signaling via Bcl-2 translocation in the PFC.