The onset of diabetic neuropathy, a complication diabetes mellitus, has been linked to poor glycemic control. We tested the hypothesis that mitogen-activated protein kinases (MAPK) form transducers for damaging effects high glucose. In cultures adult rat sensory neurons, glucose activated JNK and p38 MAPK but did not result in cell damage. However, oxidative stress ERK MAPKs resulted cellular dorsal root ganglia streptozotocin-induced rats (a model type I diabetes), were at 8 wk duration,...

The pathophysiology of dopamine dysregulation in schizophrenia involves alterations at the ventral midbrain level. Given that inflammatory mediators such as cytokines influence functional properties neurons, inflammation may play a role by contributing to presynaptic abnormalities. Thus, we quantified markers dopaminergic areas people with and matched controls. We also measured these mice exposed maternal immune activation (MIA) during pregnancy, an established risk factor for other...

Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation dopamine-related psychopathology. Evidence from adult rodent brain indicates that can modulate nigrostriatal dopamine. However, studies are required to understand role plays maturation dopamine pathways during adolescence and elucidate molecular mechanism(s) by which exerts its effects. We hypothesized indices neurotransmission [synthesis (tyrosine hydroxylase), breakdown...

Increased cytokine and inflammatory-related transcripts are found in the ventral midbrain, a dopamine neuron rich region associated with schizophrenia symptoms. In fact, half of cases can be defined as having "high inflammatory/immune biotype". Recent studies implicate both complement macrophages cortical neuroinflammation schizophrenia. Our aim was to determine whether measures related phagocytosis/macrophages (CD163, CD64, FN1), or macrophage adhesion [intercellular cell molecule 1...

Abstract Background Increased risk of schizophrenia in adolescent males indicates that a link between the development dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found most studies address this adult animals. Testosterone-dependent actions neurons direct via activation androgen receptors (AR) indirect by conversion 17β-estradiol estrogen (ER). How...

Abstract The dopamine hypothesis of schizophrenia posits that increased subcortical underpins psychosis. In vivo imaging studies indicate an presynaptic synthesis capacity in striatal terminals and cell bodies the midbrain schizophrenia; however, measures dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise dysregulation could result from changes expression enzymes, receptors, transporters or catabolic enzymes. Gene 12...

Embryonic dorsal root ganglion (DRG) neurons die after axonal damage in vivo , and cultured embryonic DRG require exogenous neurotrophic factors that activate the neuroprotective transcription factor nuclear factor-κB (NF-κB) for survival. In contrast, adult survive permanent axotomy defined culture media devoid of vitro . Peripheral rats induces local accumulation cytokine tumor necrosis α (TNFα), a potent activator NF-κB activity. We tested hypothesis activation stimulated by endogenous...

Background: Glutamatergic receptor [N-methyl-D-aspartate (NMDAR)] alterations within cortex, hippocampus, and striatum, are linked to schizophrenia pathology. Maternal immune activation (MIA) is an environmental risk factor for the development of in offspring. In rodents, gestational timing MIA may result distinct behavioural outcomes adulthood, but how impact nature extent NMDAR-related changes brain not known. We hypothesise that NMDR-related molecular rat striatum hippocampus induced by...

Abstract Reductions in the GABAergic neurotransmitter system exist across multiple brain regions schizophrenia and encompass both pre- postsynaptic components. While reduced midbrain inhibitory neurotransmission may contribute to hyperdopaminergia thought underpin psychosis schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that GABA-related markers would be found of people these correlate dopaminergic changes. downregulation neuron exacerbated...

Testosterone attenuates postnatal hippocampal neurogenesis in adolescent male rhesus macaques through altering neuronal survival. While brain-derived neurotropic factor (BDNF)/ tyrosine kinase receptor B (TrkB) are critical regulating survival, it is not known if the molecular mechanism underlying testosterone's action on involves changes BDNF/TrkB levels. First, (1) we sought to localize site of synthesis full length and truncated TrkB neurogenic regions macaque hippocampus. Next, (2) asked...

Stress and inflammation are risk factors for schizophrenia. Chronic psychosocial stress is associated with subcortical hyperdopaminergia, a core feature of Hyperdopaminergia arises from midbrain neurons, leading us to hypothesise that changes in response pathways may occur this region. To identify whether transcriptional glucocorticoid mineralocorticoid receptors (NR3C1/GR, NR3C2/MR) or other signalling molecules (FKBP4, FKBP5) exist schizophrenia midbrain, we measured gene expression the...

There is growing evidence that neuroinflammation may contribute to schizophrenia neuropathology. Elevated pro-inflammatory cytokines are evident in the midbrain from subjects, findings driven by a subgroup of patients, characterised as "high inflammation" biotype. Cytokines trigger release antibodies, which immunoglobulin G (IgG) most common. The level and function IgG regulated its transporter (FcGRT) receptors (including FcGR3A) balance with anti-inflammatory receptor FcGR2B. Testing...

Late adolescence in males is a period of increased susceptibility for the onset schizophrenia, coinciding with circulating testosterone. The cognitive deficits prevalent schizophrenia may be related to unhealthy cortical interneurons, which are trophically dependent on brain derived neurotrophic factor. We investigated, under conditions depleted (monkey and rat) replaced (rat) testosterone over adolescence, changes gene expression BDNF TrkB transcripts interneuron markers relationships...

Although sex steroids are known to modulate brain dopamine, it is still unclear how testosterone modifies locomotor behaviour controlled, at least in part, by striatal dopamine adolescent males. Our previous work suggests that increasing during adolescence may bias midbrain neurons synthesise more dopamine. We hypothesised baseline and amphetamine-induced locomotion would differ adult males depending on exposure adolescence. concomitant stimulation of estrogen receptor signaling, through a...

Abstract People with schizophrenia exhibit deficits in inhibitory neurons and cognition. The timing of maternal immune activation (MIA) may present distinct schizophrenia-like phenotypes progeny. We investigated whether early gestation [gestational day (GD) 10] or late (GD19) MIA, via viral mimetic polyI:C, produces neuron indices (GAD1, PVALB, SST, SSTR2 mRNAs) within cortical, striatal, hippocampal subregions male adult rat offspring. In situ hybridisation revealed that polyI:C offspring...

While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work shown increased circulating DHEA abnormal cortisol/DHEA ratios in people with schizophrenia, however reports limited their relationship to neuropathology is unclear. We performed the largest study date compare serum schizophrenia healthy controls, investigated extent which predict brain volume. Serum...