James P. Kesby

Developmental Vitamin D Deficiency Alters MK 801-Induced Hyperlocomotion in the Adult Rat: An Animal Model of Schizophrenia

BACKGROUND Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. METHODS Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. RESULTS DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. CONCLUSIONS These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.

Olfactory Mucosa Is a Potential Source for Autologous Stem Cell Therapy for Parkinson's Disease

Parkinsons disease is a complex disorder characterized by degeneration of dopaminergic neurons in the substantia nigra in the brain. Stem cell transplantation is aimed at replacing dopaminergic neurons because the most successful drug therapies affect these neurons and their synaptic targets. We show here that neural progenitors can be grown from the olfactory organ of humans, including those with Parkinsons disease. These neural progenitors proliferated and generated dopaminergic cells in vitro. They also generated dopaminergic cells when transplanted into the brain and reduced the behavioral asymmetry induced by ablation of the dopaminergic neurons in the rat model of Parkinsons disease. Our results indicate that Parkinsons patients could provide their own source of neuronal progenitors for cell transplantation therapies and for direct investigation of the biology and treatments of Parkinsons disease.

The effects of vitamin D on brain development and adult brain function

A role for vitamin D in brain development and function has been gaining support over the last decade. Multiple lines of evidence suggest that this vitamin is actually a neuroactive steroid that acts on brain development, leading to alterations in brain neurochemistry and adult brain function. Early deficiencies have been linked with neuropsychiatric disorders, such as schizophrenia, and adult deficiencies have been associated with a host of adverse brain outcomes, including Parkinsons disease, Alzheimers disease, depression and cognitive decline. This review summarises the current state of research on the actions of vitamin D in the brain and the consequences of deficiencies in this vitamin. Furthermore, we discuss specific implications of vitamin D status on the neurotransmitter, dopamine.

Vitamin D deficiency during various stages of pregnancy in the rat; its impact on development and behaviour in adult offspring.

Developmental vitamin D (DVD) deficiency alters brain development and behaviour in the rat. The aim of this study was to vary levels of vitamin D deficiency during gestation and examine the effects on developmental milestones and behaviour in adult offspring. By manipulating the withdrawal and reintroduction of vitamin D in the diet of female Sprague-Dawley rats, their offspring were subjected to four different prenatal vitamin D conditions: (a) control (normal vitamin D throughout gestation); (b) early-DVD deficiency; (c) late-DVD deficiency; and (d) full-DVD deficiency. We show that the standard measure for vitamin D status, 25(OH)D(3), can be significantly manipulated within 7 days by dietary intervention. We also show that levels of the active form of this vitamin, 1,25(OH)(2)D(3), replete within the same time frame as 25(OH)D(3) but are slower to deplete. Developmental milestones remained normal across all four dietary groups. Concerning the adult behavioural phenotype, both full- and late-DVD deficiency were associated with MK-801-induced hyperlocomotion. Overall, these data suggest that vitamin D deficiency restricted to late gestation only is sufficient to disrupt adult brain functioning in the rat. These findings suggest there may be a therapeutic window for maternal dietary intervention in the DVD model of psychosis.

Developmental vitamin D deficiency alters dopamine-mediated behaviors and dopamine transporter function in adult female rats

RationaleDevelopmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD deficiency in neonatal rats is associated with alterations in cellular development, dopamine metabolism, and brain morphology. DVD-deficient adult rats show novelty-induced hyperlocomotion and an enhanced locomotor response to MK-801, which can be ameliorated by pretreatment with the antipsychotic drug haloperidol.ObjectivesIn this study, we examined locomotor responses of male and female juvenile and adult rats to a dose range of amphetamine. We also measured dopamine receptor and monoamine transporter densities in adult brain.ResultsFemale DVD-deficient adult rats displayed an enhanced sensitivity to amphetamine-induced locomotion, an increased dopamine transporter density in the caudate–putamen and increased affinity in the nucleus accumbens compared with control females. By contrast, there were no differences between control and DVD-deficient male rats.DiscussionTaken together, this suggests an alteration in the development of the dopamine system and on dopamine-mediated behaviors in female DVD-deficient rats, and this may be relevant to the underlying neurobiology of schizophrenia.

Developmental vitamin D deficiency alters dopamine turnover in neonatal rat forebrain.

There is growing evidence that low vitamin D impacts adversely on brain development. The current study investigated the impact of developmental vitamin D (DVD) deficiency on dopamine and serotonin metabolism in the neonatal rat brain. DVD-deficiency resulted in an altered dopaminergic metabolic profile in the forebrain, with a decrease in the conversion of dihydroxyphenylacetic acid (DOPAC) to homovanillic acid (HVA). Correspondingly, expression of the enzyme required for this conversion, catechol-O-methyl transferase (COMT), was decreased. These results suggest that DVD-deficiency influences dopamine turnover during development.

Enduring Deficits in Brain Reward Function after Chronic Social Defeat in Rats: Susceptibility, Resilience, and Antidepressant Response

BACKGROUND Anhedonia, or diminished interest or pleasure in rewarding activities, characterizes depression and reflects deficits in brain reward circuitries. Social stress induces anhedonia and increases risk of depression, although the effect of social stress on brain reward function is incompletely understood. METHODS This study assessed the following: 1) brain reward function in rats (using the intracranial self-stimulation procedure) and protein levels of brain-derived neurotrophic factor and related signaling molecules in response to chronic social defeat, 2) brain reward function during social defeat and long-term treatment with the antidepressants fluoxetine (5 mg/kg/day) and desipramine (10 mg/kg/day), and 3) forced swim test behavior after social defeat and fluoxetine treatment. RESULTS Social defeat profoundly and persistently decreased brain reward function, reflecting an enduring anhedonic response, in susceptible rats, whereas resilient rats showed no long-term brain reward deficits. In the ventral tegmental area, social defeat, regardless of susceptibility or resilience, decreased brain-derived neurotrophic factor and increased phosphorylated AKT, whereas only susceptibility was associated with increased phosphorylated mammalian target of rapamycin. Fluoxetine and desipramine reversed lower, but not higher, stress-induced brain reward deficits in susceptible rats. Fluoxetine decreased immobility in the forced swim test, as did social defeat. CONCLUSIONS These results suggest that the differential persistent anhedonic response to psychosocial stress may be mediated by ventral tegmental area signaling molecules independent of brain-derived neurotrophic factor and indicate that greater stress-induced anhedonia is associated with resistance to antidepressant treatment. Consideration of these behavioral and neurobiological factors associated with resistance to stress and antidepressant action may promote the discovery of novel targets to treat stress-related mood disorders.

Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice

Epidemiological evidence suggests that low levels of vitamin D may predispose people to develop depression and cognitive impairment. While rodent studies have demonstrated that prenatal vitamin D deficiency is associated with altered brain development, there is a lack of research examining adult vitamin D (AVD) deficiency. The aim of this study was to examine the impact of AVD deficiency on behaviour and brain function in the mouse. Ten-week old male C57BL/6J and BALB/c mice were fed a control or vitamin D deficient diet for 10 weeks prior to, and during behavioural testing. We assessed a broad range of behavioural domains, excitatory and inhibitory neurotransmission in brain tissue, and, in separate groups of mice, locomotor response to d-amphetamine and MK-801. Overall, AVD deficiency resulted in hyperlocomotion in a novel open field and reduced GAD65/67 levels in brain tissue. AVD-deficient BALB/c mice had altered behaviour on the elevated plus maze, altered responses to heat, sound and shock, and decreased levels of glutamate and glutamine, and increased levels of GABA and glycine. By contrast C57BL/6J mice had a more subtle phenotype with no further behavioural changes but significant elevations in serine, homovanillic acid and 5-hydroxyindoleacetic acid. Although the behavioural phenotype of AVD did not seem to model a specific disorder, the overall reduction in GAD65/67 levels associated with AVD deficiency may be relevant to a number of neuropsychiatric conditions. This is the first study to show an association between AVD deficiency and prominent changes in behaviour and brain neurochemistry in the mouse.

Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring

RationaleDevelopmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to amphetamine-induced locomotion in female DVD-deficient rats but not in male DVD-deficient rats and an enhanced locomotor response to the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density.MethodsDVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort.ResultsDVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes.ConclusionsThese results suggest that a transient prenatal vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders.

Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia

Schizophrenia is a heterogeneous group of disorders with unknown etiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine (DA) neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesized that abnormal DA signaling in the adult patient may result from altered DA signaling during fetal brain development. Environmental and genetic risk factors can be modeled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the etiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD) deficiency. DVD-deficient adult rats display an altered behavioral profile in response to DA releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis, and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters DA metabolism in the developing brain. We speculate such alterations in fetal brain development may change the trajectory of DA neuron ontogeny to induce the behavioral abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in DA ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.