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Since the discovery of ketamine anti-depressant effects in last decade, it has effectively revitalized interest in investigating excitatory synapses hypothesis in the pathogenesis of depression. In the present study, we aimed to reveal the excitatory synaptic regulation of corticotropin-releasing hormone (CRH) neuron in the hypothalamus, which is the driving force in hypothalamic-pituitary-adrenal (HPA) axis regulation. This study constitutes the first observation of an increased density of PSD-93-CRH co-localized neurons in the hypothalamic paraventricular nucleus (PVN) of patients with major depression. PSD-93 overexpression in CRH neurons in the PVN induced depression-like behaviors in mice, accompanied by increased serum corticosterone level. PSD-93 knockdown relieved the depression-like phenotypes in a lipopolysaccharide (LPS)-induced depression model. Electrophysiological data showed that PSD-93 overexpression increased CRH neurons synaptic activity, while PSD-93 knockdown decreased CRH neurons synaptic activity. Furthermore, we found that LPS induced increased the release of glutamate from microglia to CRH neurons resulted in depression-like behaviors using fiber photometry recordings. Together, these results show that PSD-93 is involved in the pathogenesis of depression via increasing the synaptic activity of CRH neurons in the PVN, leading to the hyperactivity of the HPA axis that underlies depression-like behaviors.

Peripheral nerve elongation by a tissue expander may offer an alternative to nerve grafting in the management of segmental nerve loss. We investigated the morphological changes in peripheral nerve following slow nerve elongation by laser Doppler flowmetry controlled expansion in a rabbit sciatic nerve model. The animals were randomly assigned to one of four groups, with an expander volume of 0, 5, 10 or 15 cm3, respectively. An elongation of up to 40% was possible with preservation of clinical function. Nerve conduction velocity decreased in relation to elongation. Paranodal widening, followed by remyelination of the node, were early and constant morphological features. Demyelination and remyelination of whole internodes, and axonal degeneration occurred sporadically and did not correlate with elongation, rate of elongation or neurophysiological parameters. The model of laser Doppler flowmetry controlled nerve expansion provides a method for remodelling of myelin sheaths and lengthening of nerve fibers without axonal damage.

Alzheimer's disease is characterized neuropathologically by senile plaques and cytoskeletal changes. It has been proposed that amorphic plaques would locally induce anterograde propagation of cytoskeletal changes in consecutive neurons followed by amorphic plaque deposition at their axonal terminals. The Alzheimer changes would spread in this way along neural pathways. To test the 'primary amyloid anatomical cascade hypothesis', Congo red staining, beta-protein/A4 (Abeta) antiserum and Alz-50, which recognizes cytoskeletal changes, were applied to the hypothalamus and adjoining brain areas of five Alzheimer's disease patients of 40-90 years of age and five age- and sex-matched controls. The results showed that (1) virtually all Abeta plaques in the hypothalamus were of the Congo red-negative amorphic type; (2) amorphic plaques and Alz-50-stained cytokeletal changes were observed not only in all Alzheimer's disease patients but also in a non-demented, 90-year-old control subject; (3) the density of amorphic plaques in the hypothalamus was unrelated to the duration of the dementia; (4) the density of amorphic plaques was unrelated to that of Alz-50-stained cytoskeletal changes; (5) double-labeling with anti-Abeta and Alz-50 did not show an evident topical relationship between amorphic plaque deposition and the occurrence of cytoskeletal changes; and (6) the distribution of Abeta and Alz-50 staining in five brain areas, for which essential anatomical information is available, did not support the primary amyloid anatomical cascade hypothesis. Amorphic plaques and cytoskeletal changes rather occur independently.

According to the literature, only minor nonspecific histopathological lesions are present in the motor cortex in up to 90% of the amyotrophic lateral sclerosis (ALS) patients. These observations, however, have so far been based mainly on conventional staining techniques. An exception to this is the focal glial reaction that has been reported following immunocytochemical staining for glial fibrillary protein (GFAP), which is reported to be distinctive for ALS in the cortex. Since perikarya of degenerating motor neurons in the spinal cord of ALS patients have been found to accumulate phosphorylated neurofilaments (PNF), an investigation was conducted to determine whether PNF was also a sensitive marker for alterations in the motor cortex in this condition. On large brain sections from 15 ALS patients, intense PNF immunoreactivity was found in the motor cortex from 11 patients. It was mainly localized in small pyramidal cells and basket cells, whereas only slight staining was observed in Betz cells. PNF-positive basket cells were also present in controls, but the basket cells staining for PNF were less numerous in controls than in ALS specimens. PNF-positive Betz cells were found in 47% of 15 ALS patients and in 10% of the controls. PNF accumulation was also found in swollen, probably degenerating, terminal boutons around perikarya of large pyramidal cells and Betz cells in the motor areas of ALS patients only. These observations suggest that the premotor innervation of the motor system is preferentially affected in ALS. Small brain sections, comprising the motor cortex, from 18 additional ALS patients demonstrated a similar PNF-staining pattern. However, differentiating ALS patients from controls was much easier when studying large brain sections. No ubiquitin-immunoreactive inclusions were found, except for sporadic tangles. The presence of a focal-GFAP positive astrocytosis as reported in the literature in the precentral cortex was confirmed. However, it was found to be nonspecific since it was also present outside the precentral cortex and in the cortex of normal control patients. No spatial relation was found between the distribution of the glial reaction in ALS and the areas containing neurons and boutons accumulating PNF.