Biomedical subjects

John D Elsworth

Publications and source records attributed to John D Elsworth.

12 recordsLinked to original sources

PubMed2006

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite.

The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.

Action Potentials↗

PubMed2006

Uncoupling protein-2 promotes nigrostriatal dopamine neuronal function.

Uncoupling protein 2 (UCP2) is known to promote neuroprotection in many forms of neurological pathologies including Parkinson's disease. Here, we examined the hypothesis that UCP2 also mediates aspects of normal nigrostriatal dopamine (DA) function. Mice lacking UCP2 exhibited reduced dopamine turnover in the striatum as measured by the 3,4-dihydoxyphenylacetic acid/dopamine (DOPAC/DA) ratio, reduced tyrosine hydroxylase immunoreactivity (TH IR) in the substantia nigra pars compacta (SNc) and reticulata, striatum and nucleus accumbens. UCP2-knockout (KO) mice also had reduced dopamine transporter immunoreactivity (DAT IR) in the SNc but not other brain regions examined. In order to determine if these biochemical deficits are transcribed into behavioural deficits, we examined locomotor function in UCP2-KO mice compared to wild-type (WT) controls. UCP2-KO mice exhibited significantly reduced total movement distance, movement velocity and increased rest time compared to wild-type controls. These results suggest that UCP2 is an important mitochondrial protein that helps to maintain normal nigrostriatal dopamine neuronal function and a reduction in UCP2 levels may predispose individuals to environmental causes of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2005

Partial dopamine loss enhances activated caspase-3 activity: differential outcomes in striatal projection systems.

Parkinson's disease (PD) is a basal ganglia disorder. Motor symptoms develop insidiously following substantial neurodegeneration of the dopamine (DA) neurons in the nigrostriatal system and produce slowed, infrequent movements, postural instability, and gait changes. A thorough understanding of neurochemical compensations occurring in the striatum during early stages of PD is crucial in identifying components that are altered initially as the DA is depleted. Producing an incomplete lesion of the nigrostriatal DA system in rats would mimic the principal early neurochemical features of human PD. We infused 6-hydroxydopamine unilaterally into the substantia nigra to reach a target of approximately 50% depletion in striatal DA at 4 weeks. This was evaluated by HPLC analysis of tissue DA content and monitored behaviorally by forepaw use reflecting asymmetries in striatal DA levels. DA loss was assessed by using tyrosine hydroxylase immunohistochemical staining, and the data were conjoined with the behavioral assessments. We found that activated caspase-3, its actin cleavage product fractin, and components of the apoptosome were increased significantly in DA-depleted striatum. Thus mobilization of the intrinsic programmed cell death pathway occurred, without cell loss. Elevations in apoptogenic proteins were pronounced in enkephalinergic striatopallidal neurons compared with the substance P-containing striatonigral neurons. Our findings suggest that cellular homeostatic imbalances that accompany even mild striatal DA depletion take time to develop, differentially affect the striatal output pathways, and may be an important feature of early-stage PD. These observations could be capitalized upon to develop therapeutic interventions in the preclinical phases of the disorder.

Animals↗

PubMed2005

Development of A9/A10 dopamine neurons during the second and third trimesters in the African green monkey.

Disruption in the development of dopamine-containing neurons has been postulated to underlie several CNS disorders. However, there have been no quantitative studies on the normal development of primate dopamine neurons. Thus, the fetal maturation of primate midbrain dopamine neurons was examined to establish changes that occur in the A9/A10 groups during the second and third trimesters. Eleven fetal African green monkey midbrains were immunostained for tyrosine hydroxylase (TH-ir) as a marker for dopamine neurons and quantified using stereological techniques (nucleator method). The number and size of defined dopamine neurons and the volume occupied by A9/A10 neurons increased in near linear fashion throughout the term. The estimated number of defined dopamine neurons in each hemisphere rose from approximately 50,000 at embryonic day (E) 70 to 225,000 at birth (E165), similar to the adult population. The size and the area occupied by them at birth were, however, well below the estimated adult levels. Additionally, the younger fetal midbrains had far less diversity in dopamine cell volumes compared with older fetuses and adult brains. Until midway through gestation (E81), clusters of apparently immature midbrain TH-ir cells were observed, but could not be counted. Even though the majority of cells destined to become dopamine neurons are generated in the first trimester, phenotypical maturation of A9 and A10 cell bodies continues steadily throughout gestation and extends well into the postnatal period. These data have relevance to transplantation studies that employ fetal dopaminergic grafts, and to disorders hypothesized to result from damage to developing midbrain dopamine neurons.

Analysis of Variance↗

PubMed2005

Prenatal exposure to cocaine selectively disrupts the development of parvalbumin containing local circuit neurons in the medial prefrontal cortex of the rat.

Exposure to cocaine in utero can result in cognitive deficits potentially through a disruption in the inhibitory processes of the frontal cortex. One potential mechanism is through alterations in the inhibitory local circuit neurons containing the calcium-binding protein, parvalbumin. Parvalbumin-immunostaining primarily identifies 2 types of local circuit neurons: larger, rounder, axo-somal basket cells and smaller, more-spindle shaped, axo-axonic chandelier cells. Both are thought to have critical impact on the excitatory/inhibitory balance due to the proximal site of projection on pyramidal neurons. Calretinin, another calcium-binding protein, identifies a distinct sub-population of inhibitory local circuits that impinges more distally on the dendritic arbor and serves as a control population for this study. Here, we examine local circuit neurons containing either parvalbumin or calretinin in adolescent male rats (approximately 45 days old) exposed to saline or cocaine (3 mg/kg, intravenous twice a day during embryonic days 10 to 20). Prenatal cocaine exposure caused select changes in the parvalbumin, but not calretinin, containing cells in the frontal cortex. Specifically, prenatal cocaine exposure is associated with a 50% reduction in spindle-shaped parvalbumin-immunoreactive cells potentially indicating a select loss of chandelier cells or a shift to a rounder shape. Additionally, a reduction in the number of dendrites of parvalbumin-immunoreactive cells in rats exposed to cocaine in utero was noted. Other measures of both parvalbumin- and calretinin-immunoreactive cells were unchanged, including total number of cells, distribution by depth, and sizes of cells. These changes to the excitatory/inhibitory balance in the frontal cortex may contribute to the cognitive deficits associated with prenatal cocaine exposure.

Animals↗

PubMed2003

Axo-axonic structures in the medial prefrontal cortex of the rat: reduction by prenatal exposure to cocaine.

The cognitive deficits associated with prenatal exposure to cocaine have been hypothesized to be the results of changes in the anatomy and function of the frontal cortex. In this study, pregnant dams were treated with cocaine (3 mg/kg i.v. twice a day) and the resulting adolescent (postnatal day, approximately 45) male offspring were killed for immunocytochemical determination of the total linear measure, number, location, and lengths of inhibitory GABA transporter-1 immunoreactive axo-axonic structures commonly called "candles" or "cartridges" in the medial prefrontal cortex. These inhibitory structures are the axon terminals of GABAergic cells that impinge on the initial axon segments of excitatory pyramidal neurons. We report that prenatal cocaine exposure decreased the number of these inhibitory candles. The greatest reduction of candles was observed in the ventral prelimbic cortex. Additionally, there was a subtle difference in the pattern of distribution of candles, namely the depth of the initial candle in the ventral portions of the prefrontal cortex was greater in rats exposed to prenatal cocaine. However, there was no overt change in the number of cells that were immunoreactive for the calcium-binding protein parvalbumin, an indicator of a subset of GABAergic interneurons that includes axo-axonic chandelier cells. We conclude that exposure to cocaine in utero disrupts the development of the axo-axonic cells in the prefrontal cortex and this disruption could contribute to the cognitive deficits reported with prenatal cocaine exposure.

Animals↗

PubMed2003

Coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss in a primate model of Parkinson's disease.

Parkinson's disease is characterized by dopamine cell loss of the substantia nigra. Parkinson's disease and the neurotoxin 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine may destroy dopamine neurons through oxidative stress. Coenzyme Q is a cofactor of mitochondrial uncoupling proteins that enhances state-4 respiration and eliminate superoxides. Here we report that short-term oral administration of coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine administration in monkeys.

Animals↗

PubMed2002

Selective activation of the A10, but not A9, dopamine neurons in the rat by the predator odor, 2,5-dihydro-2,4,5-trimethylthiazoline.

2,5-Dihydro-2,4,5-trimethylthiazoline (TMT), a predator odor, has many similar attributes to classic stresses, including activation of cortical dopamine (DA) turnover. Here, we report that exposure to TMT resulted in the expression of c-fos, an immediate-early gene, in A10, but not A9, DA neurons using immunocytochemical techniques. The magnitude of TMT-associated Fos expression was less than that seen with intermittent, mild footshock. Exposure to the control odor, butyric acid, did not result in the increase of expression of Fos protein. Fos is thought to be involved with long-term changes in a neuron's structure and function that may underlie learning by altering the expression of other genes with AP-1 sites. Exposure to TMT may result in alterations in the A10 neurons that could contribute to an altered response to subsequent stresses.

Animals↗

PubMed2002

Prenatal cocaine exposure disrupts non-spatial, short-term memory in adolescent and adult male rats.

The rise in the recreational use of cocaine in the last two decades has resulted in a growing health concern about fetal drug exposure. In exposed children, investigators have noted altered cognitive performance in complex or distracting, but not more controlled, situations. In rodent models, deficits in short-term memory have been noted in some, but not all, paradigms, although these studies also differ in routes of administration and dosing models. Here, we report short-term memory deficits in rats prenatally exposed to cocaine using an intravenous administration model to closer mimic cocaine doses and pharmacokinetics seen with human use. A spontaneous two object recognition task was used to avoid (1) clearly aversive or rewarding components, (2) reference memory component and (3) the use of external motivators, such as swimming stress or food deprivation/rewards. In this task, adolescent and adult male rats exposed to cocaine in utero demonstrated deficits in short-term memory compared with saline controls. No difference in the time spent exploring the objects or the number of failures was noted between the prenatal cocaine and saline rats. This study suggests that prenatal exposure to cocaine can result in a long-lasting deficit in non-spatial, short-term memory in a spontaneously performed task.

Aging↗

PubMed2002

Embryonic ventral mesencephalic grafts to the substantia nigra of MPTP-treated monkeys: feasibility relevant to multiple-target grafting as a therapy for Parkinson's disease.

Transplantation of embryonic dopamine (DA) neurons is being studied as an experimental replacement therapy for the DA-deficiency characteristic of Parkinson's disease. Some studies suggest that one of the limitations of this approach is that intrastriatal placement of implants fails to consistently restore completely normal movement. One potential cause of this suboptimal therapeutic outcome is that changes in the neural activity of several structures in the basal ganglia circuitry resulting from striatal DA depletion is not adequately normalized by graft-derived DA replacement in striatum alone. In the present study, we assessed the feasibility of grafting embryonic DA neurons into the substantia nigra (SN) of adult parkinsonian monkeys as an approach to restoration of the DA modulation of striatal-nigral afferents that is lost after degeneration of SN neurons. Sixteen St. Kitts African green monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) received implants of embryonic monkey ventral mesencephalon (VM), or sham implants, aimed at the rostral SN. At 6 months after grafting, staining for tyrosine hydroxylase (TH) indicated that grafted DA neurons survived at this site, albeit often in reduced numbers compared with VM grafts to striatum. Grafted neurons extended neurites into the parenchyma of the SN, but there was no evidence of lengthy extension of graft-derived neurites rostrally along the trajectory of the mesostriatal fiber system. A region-specific, modest increase in DA levels and TH-positive fiber density in the ventral-medial putamen was detected, accompanied by modest but significant decreases in parkinsonian behaviors at 5-6 months after grafting. Our findings support the view that grafting embryonic tissue to the SN is a feasible procedure in nonhuman primates that provides a modest but detectable benefit of its own. These results encourage the further development of multiple-target grafting strategies as a means of restoring modulation of anatomically widespread basal ganglia structures relevant to treatment of Parkinson's disease.

Animals↗

PubMed2002

Fear-like biochemical and behavioral responses in rats to the predator odor, TMT, are dependent on the exposure environment.

Several laboratories have reported that exposure to predator odor can result in stress-like effects in rodents. While some laboratories have reported fear-like alterations in behavior, other laboratories, including our own, have failed to consistently observe fearful behaviors in rats exposed to the predator odor TMT. One potential contributing factor to this discrepancy is the handling of the rat and its test environment. In the current report, we examine biochemical, endocrinological, and behavioral effects of TMT in two distinct open fields: one small, familiar, and dimly lit, while the other was large, novel, and brightly lit. Only exposure to TMT in the large, novel open field resulted in fearful behavior; however, no increase in dopamine turnover was noted compared to no odor and control odor rats. As expected, the different open fields resulted in some biochemical and behavioral differences, including more horizontal locomotion and less grooming, higher serum corticosterone, and increased dopamine turnover in the ventral prefrontal cortex in the large open field. Finally, compared to the same open field controls, TMT exposure elevated rat serum corticosterone levels in both open fields and dopamine turnover in the dorsal and ventral medial prefrontal cortex and amygdala of rats only in the small, familiar open field. These results indicate that the TMT-induced biochemical activation of may occur without detectable fearful behaviors and may indicate a mechanism that prepares the animal for the expression of a fearful response if additional provocative stimuli are present.

Amygdala↗

PubMed2002

Male rats exposed to cocaine in utero demonstrate elevated expression of Fos in the prefrontal cortex in response to environment.

Prenatal cocaine exposure has been associated with disruption in attention and short-term memory in exposed children and in animal models. The biochemical change or changes responsible for these cognitive deficits are not known. An intriguing possibility, however, is that cocaine exposure during development disrupts the morphology or function of the frontal cortex, a region thought to contribute to cognitive and executive functions. In this report, we examined the effects of intravenous prenatal cocaine exposure on the expression of the immediate-early gene, c-fos, in the adolescent offspring to determine potential sites of disruption. The expression of Fos protein was similar in unhandled rats prenatally treated with saline or cocaine. Prenatal cocaine exposed rats that were handled, but not footshocked, however, demonstrated a dramatic selective increase in Fos expression in the ventral and medial prefrontal cortex. A footshock-induced increase in Fos expression in the prefrontal cortex was noted in prenatal saline, but not prenatal cocaine rats. Interestingly, no differences were noted in baseline or footshock-induced increased Fos expression in nuclei of the amygdala in prenatal cocaine and prenatal saline rats, indicating some aspect of the central response to stress appear unchanged. The unusual activation of the neurons of the medial and ventral prefrontal cortex may be a consequence of in utero cocaine exposure that contributes to the reported deficit in cognition.

Animals↗