Structural And Chemical Organization Of The Rat Interpeduncular Nucleus

The structural and chemical organization of the rat interpeduncular nucleus (IPN) was examined employing wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) and immunohistochemistry at the light and electron microscope level. The topographical and ultrastructural arrangements of habenular efferents innervating the IPN were studied using stereotaxic placements of WGA-HRP. The medial habenula provided a prominent afferent input to the many IPN subnuclei, with the lateral and rostral subnuclei receiving a predominantly ipsilateral input, and the intermediate, central and dorsomedial subnuclei receiving a symmetrical projection. Habenular terminals formed distinct axodendritic synapses in the rostral, lateral, intermediate and central subnuclei.;Projections of the fasciculus retroflexus (FR) were stained immunohistochemically for choline acetyltransferase (ChAT) or substance P (SP). These inputs were topographically organized among the IPN subnuclei, such that ChAT-positive axons innervated the rostral, intermediate and central subnuclei, and SP-positive inputs terminated in the lateral, dorsomedial and rostral subnuclei. Characteristic axodendritic synapses of the intermediate, central and rostral subnuclei were composed of ChAT-positive terminals, and those in the lateral, rostral and dorsomedial subnuclei were composed of SP-positive terminals.;A prominent population of neurons and an extensive plexus of axons and terminals stained immunohistochemically for glutamic acid decarboxylase (GAD) were present in the rostral, lateral, central and intermediate subnuclei. Axodendritic and axosomatic synapses possessing GAD immunoreactivity pre - and/or postsynaptically were evident in these subnuclei. GAD-immunoreactive dendrites in the intermediate, central and rostral subnuclei also received ChAT-positive terminals, and those in the lateral subnucleus received SF-positive terminals. SP-positive dendrites in the rostral subnucleus were also in receipt of ChAT-positive terminals.;The IPN is considered to be an important link between the septohabenular circuit of the limbic forebrain and several raphe and tegmental centres of the hindbrain. Neurons of the IPN are in receipt of descending habenular projections which provide putative excitatory inputs, as well as intrinsic, putative inhibitory inputs. The integration of habenular inputs with those arising from intrinsic sources may play an important role in the direct and transsynaptic modulation of projection neurons of the IPN which provide afferent inputs to the raphe and tegmental centres of the hindbrain

BACE1 activity impairs neuronal glucose oxidation:rescue by beta-hydroxybutyrate and lipoic acid

Glucose hypometabolism and impaired mitochondrial function in neurons have been suggested to play early and perhaps causative roles in Alzheimer's disease (AD) pathogenesis. Activity of the aspartic acid protease, beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), responsible for beta amyloid peptide generation, has recently been demonstrated to modify glucose metabolism. We therefore examined, using a human neuroblastoma (SH-SY5Y) cell line, whether increased BACE1 activity is responsible for a reduction in cellular glucose metabolism. Overexpression of active BACE1, but not a protease-dead mutant BACE1, protein in SH-SY5Y cells reduced glucose oxidation and the basal oxygen consumption rate, which was associated with a compensatory increase in glycolysis. Increased BACE1 activity had no effect on the mitochondrial electron transfer process but was found to diminish substrate delivery to the mitochondria by inhibition of key mitochondrial decarboxylation reaction enzymes. This BACE1 activity-dependent deficit in glucose oxidation was alleviated by the presence of beta hydroxybutyrate or α-lipoic acid. Consequently our data indicate that raised cellular BACE1 activity drives reduced glucose oxidation in a human neuronal cell line through impairments in the activity of specific tricarboxylic acid cycle enzymes. Because this bioenergetic deficit is recoverable by neutraceutical compounds we suggest that such agents, perhaps in conjunction with BACE1 inhibitors, may be an effective therapeutic strategy in the early-stage management or treatment of AD

Astrocyte scar formation aids central nervous system axon regeneration

Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration