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Biomedical subjects

Terry E Robinson

Publications and source records attributed to Terry E Robinson.

14 recordsLinked to original sources
PubMed2025

Novel insights into the genetic architecture and mechanisms of host/microbiome interactions from a multi-cohort analysis of outbred laboratory rats.

The intestinal microbiome influences health and disease. Its composition is affected by host genetics and environmental exposures. Understanding host genetic effects is critical but challenging in humans, due to the difficulty of detecting, mapping and interpreting them. To address this, we analysed host genetic effects in four cohorts of outbred laboratory rats exposed to distinct but controlled environments. We found that polygenic host genetic effects were consistent across environments. We identified three replicated microbiome-associated loci, one of which involved a sialyltransferase gene and Paraprevotella. We found a similar association in a human cohort, between ST6GAL1 and Paraprevotella, both of which have been linked with immune and infectious diseases. Moreover, we found evidence of indirect genetic effects on microbiome phenotypes, which substantially increased their total genetic variance. Finally, we identified a novel mechanism whereby indirect genetic effects can contribute to "missing heritability".

Journal Article↗
PubMed2003

Environmental complexity has different effects on the structure of neurons in the prefrontal cortex versus the parietal cortex or nucleus accumbens.

Complex housing has been used widely as a model of experience-dependent change. Animals housed in complex environments typically show synaptogenesis throughout the sensory and motor cortex as well as the striatum and hippocampus, and thus it is generally assumed that such changes are likely to be found throughout the cerebrum. The purpose of the present study was to determine whether persistent alterations of dendritic morphology would be found in two regions that had previously not been examined, namely, the medial prefrontal region (Cg3) and nucleus accumbens (NAcc). The results show that housing female rats in complex environments for 3.5 months increased dendritic arborization on medium spiny neurons in the NAcc and on pyramidal cells in the somatosensory cortex (Par 1), but not in Cg3. Environmental complexity increased spine density in all three areas, however. The failure to find increased dendritic length or branching in Cg3 was unexpected. Thus, the data suggest that complex housing may not engage prefrontal neurons in the same manner as neurons in sensory or motor areas. It appears that complex housing may not produce generalized changes in cerebral morphology. The data further suggest that it is prudent to measure both dendritic length and spine density in studies of experience-dependent effects on synaptic plasticity.

Animals↗
PubMed2003

The location of persistent amphetamine-induced changes in the density of dendritic spines on medium spiny neurons in the nucleus accumbens and caudate-putamen.

Repeated intermittent treatment with amphetamine increases the density of dendritic spines on medium spiny neurons (MSNs) in the nucleus accumbens (NAcc). The purpose of this study was two-fold: (1) to determine whether amphetamine has similar effects on MSNs in the caudate-putamen (CPu) and (2) to determine if this effect is localized to distal dendrites, the site of convergence of dopamine (DA) and glutamate synapses in the striatum. An amphetamine treatment regimen that produced behavioral sensitization increased the density of dendritic spines on MSNs in both the NAcc and dorsolateral CPu. This effect was long lasting, because it was evident 3.5 months after the discontinuation of drug treatment. The increase in spine density was confined to distal dendrites of MSNs, and was not apparent on dendrites close to the cell body. It is concluded that amphetamine may preferentially reorganize synapses at the site of DA-glutamate interaction in the striatum, which may alter DA-glutamate signaling and thereby contribute to some of the persistent behavioral and psychological consequences of repeated exposure to psychostimulant drugs.

Amphetamine↗
PubMed2003

Effects of maternal separation on behavioural sensitization produced by repeated cocaine administration in adulthood.

We examined whether early maternal separation influenced the susceptibility to behavioural sensitization produced by repeated intravenous (i.v.) injections of cocaine in adult female rats. For the first 21 days of life litters were separated from their mother for either 15 min (MS-15) or 180 min/day (MS-180). Control animals were subjected only to regular cage changes (animal facility reared; AFR). In adulthood, these three groups did not differ in their locomotor response to placement in a novel environment or to an acute i.v. injection of cocaine. After six additional daily injections of either saline or cocaine and following a 7-day drug-free interval, sensitization was assessed by giving all rats a challenge i.v. injection of cocaine. Rats exposed to either period of maternal separation (MS-15 or MS-180) showed significantly less robust sensitization than AFR rats. Therefore, early maternal separation decreased susceptibility to behavioural sensitization produced by cocaine in adulthood and the specific duration of maternal separation had no effect on this outcome.

Animals↗
PubMed2003

Amphetamine-induced c-fos mRNA expression in the caudate-putamen and subthalamic nucleus: interactions between dose, environment, and neuronal phenotype.

When administered in a novel environment relatively low doses of amphetamine induce c-fos mRNA in the subthalamic nucleus (STN) and in preproenkephalin mRNA-containing (ENK+) neurons in the caudate-putamen (CPu). When administered at home, however, low doses of amphetamine do not produce these effects. Environmental novelty also facilitates the behavioral effects of acute and repeated amphetamine, but this is dose-dependent. The purpose of the present experiment therefore was to determine if the effect of context on amphetamine-induced c-fos expression is also dose-dependent. It was found that: (i) No dose of amphetamine tested (1-10 mg/kg) induced c-fos in many ENK+ cells when given at home. (ii) When given in a novel environment low to moderate doses of amphetamine (1-5 mg/kg) induced c-fos in substantial numbers of ENK+ cells, but the highest dose examined (10 mg/kg) did not. (iii) Environmental novelty enhanced the ability of low to moderate doses of amphetamine to induce c-fos in the STN, but the highest dose of amphetamine induced robust c-fos mRNA expression in the STN regardless of context. The results do not support the idea that engaging ENK+ cells, at least as indicated by c-fos mRNA expression, is critical to produce robust behavioral sensitization, but do suggest a possible role for the STN. Furthermore, the results highlight the importance of drug-environment interactions on the neurobiological effects of drugs, and have implications for thinking about the circuits by which context modulates the acute and long-lasting consequences of amphetamine treatment.

Amphetamine↗
PubMed2003

An automated approach to quantitative air trapping measurements in mild cystic fibrosis.

PURPOSE: To automatically derive the degree of air trapping in mild cystic fibrosis (CF) disease from high-resolution CT (HRCT) data, and to evaluate the discriminating power of the measurement. MATERIALS AND METHODS: The data consist of six pairs of anatomically matched tomographic slices, obtained during breath-holding in triggered HRCT acquisitions. The pairs consist of an inspiratory slice, at > or = 95% of slow vital capacity, and an expiratory slice at near residual volume (nRV). The subjects are 25 patients with mild CF and 10 age-matched, normal control subjects. SUBJECTS: Lung segmentation is automatic. The limits defining air trapping in the expiratory slices are determined by the distribution of densities in the expanded lung. They are modulated by density changes between expiration and inspiration. Air trapping defects consist of contiguous low-density voxels. The difference between patients and control subjects was evaluated in comparison to pulmonary function test (PFT) results and lung density distribution descriptors (global density descriptors). RESULTS: In mild CF, air trapping does not correlate with global PFT results, except for the ratio of residual volume (RV) to total lung capacity (TLC); however, the size of air trapping defects was the best discriminator between patients and control subjects (p < 0.005). Of PFT results, only RV/TLC reached significance at p < 0.05. The global density descriptors reached near significance in the nRV images only. CONCLUSION: Air trapping defined as defect size and measured in an objective automated manner is a powerful discriminator for mild CF.

Adolescent↗
PubMed2002

Widespread but regionally specific effects of experimenter- versus self-administered morphine on dendritic spines in the nucleus accumbens, hippocampus, and neocortex of adult rats.

We studied the effects of self-administered (SA) vs. experimenter-administered (EA) morphine on dendritic spines in the hippocampal formation (CA1 and dentate), nucleus accumbens shell (NAcc-s), sensory cortex (Par1 and Oc1), medial frontal cortex (Cg3), and orbital frontal cortex (AID) of rats. Animals in the SA group self-administered morphine in 2-h sessions (0.5 mg/kg/infusion, i.v.) for an average of 22 sessions and animals in the EA group were given daily i.v. injections of doses that approximated the total session dose for matched rats in Group SA (average cumulative dose/session of 7.7 mg/kg). Control rats were given daily i.v. infusions of saline. One month after the last treatment the brains were processed for Golgi-Cox staining. In most brain regions (Cg3, Oc1, NAcc-s) morphine decreased the density of dendritic spines, regardless of mode of administration (although to a significantly greater extent in Group SA). However, only SA morphine decreased spine density in the hippocampal formation and only EA morphine decreased spine density in Par1. Interestingly, in the orbital frontal cortex morphine significantly increased spine density in both Groups SA and EA, although to a much greater extent in Group SA. We conclude: 1) Morphine has persistent (at least 1 month) effects on the density of dendritic spines in many brain regions, and on many different types of cells (medium spiny neurons, pyramidal cells, and granule cells); 2) The effect of morphine on spine density (and presumably synaptic organization) varies as a function of both brain region and mode of drug administration; and 3) The ability of morphine to remodel synaptic inputs in a regionally specific manner may account for the many different long-term sequelae associated with opioid use.

Animals↗
PubMed2002

Locomotor sensitization to cocaine is associated with increased Fos expression in the accumbens, but not in the caudate.

Behavioral sensitization following repeated intermittent cocaine administrations is thought to involve alterations in cocaine regulation of neural activity within the accumbens and caudate brain regions. Although Fos immunohistochemistry and c-fos in situ hybridization have frequently been used to assess changes in cocaine-induced neural activity following prior cocaine exposure, these techniques have rarely been used to examine neural activity in the accumbens of behaviorally sensitized animals. In the present experiment, we compared the ability of increasing doses of cocaine to induce Fos in the accumbens and caudate of rats following a treatment procedure (7 once daily injections of 15 mg/kg of cocaine or the saline vehicle) shown to produce robust and persistent (1 week) locomotor sensitization. In sensitized animals, there was a leftward shift in the dose-response curve for cocaine induction of Fos in the accumbens, but not in the caudate. These results provide the first parametric evidence for sensitization of cocaine-induced Fos expression in the accumbens.

Animals↗
PubMed2002

A 6-hydroxydopamine lesion of the mesostriatal dopamine system decreases the expression of corticotropin releasing hormone and neurotensin mRNAs in the amygdala and bed nucleus of the stria terminalis.

The mesostriatal dopamine (DA) system is known to play a vital role in extrapyramidal motor responses, and animals with a unilateral 6-hydroxydopamine (6-OHDA) lesion of this system have proved useful in studying the behavioral and neurobiological effects of DA depletion. Less is known about the role of this system in modulating emotional responses, although a number of lines of evidence suggest that dopamine influences emotional behavior. During the course of a study involving rats that had a unilateral 6-OHDA lesion, we discovered a hemispheric asymmetry in the levels of corticotropin releasing hormone (CRH) mRNA in the central nucleus of the amygdala (CEA). The present study was performed in order to determine (1) if the lesion resulted in a decrease in CRH mRNA, and/or if there was upregulation on the intact side, (2) if a similar imbalance in CRH mRNA was observed in other brain regions and (3) if levels of other neuropeptide mRNAs were affected by the lesion. Adult male Sprague-Dawley rats were left unoperated or were pretreated with desipramine and then injected unilaterally with 6-OHDA into the medial forebrain bundle to lesion the ascending mesostriatal DA neurons. Animals were killed 15-31 days following surgery and brain sections processed for CRH, neurotensin and enkephalin mRNAs by in situ hybridization. Levels of CRH and neurotensin mRNAs were decreased on the lesioned side in the CEA and oval nucleus of the BST (BSTov) relative to the intact side and to unoperated controls. Levels of enkephalin mRNA in these regions were not affected by the lesion. These effects appeared specific, because the lesion did not alter CRH mRNA expression in the ventral BST, paraventricular nucleus of the hypothalamus or cortex or neurotensin mRNA expression in the CA1 region of the hippocampus. In contrast, and consistent with previous reports, levels of neurotensin and enkephalin mRNAs were upregulated on the lesioned side of the striatum. This study provides evidence that the mesostriatal DA system regulates CRH and neurotensin mRNA in the BSTov and CEA, suggesting that dopamine may be an important modulator of CRH and neurotensin function within these nuclei. Although the precise mechanisms are not clear, and the involvement of noradrenergic systems cannot be precluded, data are consistent with the idea that dopamine, released in response to a stressful experience for example, interacts with CRH and neurotensin in the extended amygdala to affect emotional responsiveness.

Amygdala↗
PubMed2002

Addiction.

The development of addiction involves a transition from casual to compulsive patterns of drug use. This transition to addiction is accompanied by many drug-induced changes in the brain and associated changes in psychological functions. In this article we present a critical analysis of the major theoretical explanations of how drug-induced alterations in psychological function might cause a transition to addiction. These include: (a) the traditional hedonic view that drug pleasure and subsequent unpleasant withdrawal symptoms are the chief causes of addiction; (b) the view that addiction is due to aberrant learning, especially the development of strong stimulus-response habits; (c) our incentive-sensitization view, which suggests that sensitization of a neural system that attributes incentive salience causes compulsive motivation or "wanting" to take addictive drugs; and (d) the idea that dysfunction of frontal cortical systems, which normally regulate decision making and inhibitory control over behavior, leads to impaired judgment and impulsivity in addicts.

Animals↗
PubMed2002

The rate of intravenous cocaine administration determines susceptibility to sensitization.

The potential for addiction is thought to be greatest when drugs of abuse reach the brain rapidly, because this produces intense subjective pleasurable effects. However, the ability of drugs to induce forms of cellular plasticity related to behavioral sensitization may also contribute to addiction. Therefore, we studied the influence of rate of intravenous cocaine delivery on its ability to induce psychomotor sensitization. In one experiment, rotational behavior in rats with a unilateral 6-hydroxydopamine lesion was used as an index of psychomotor activation, and in a second experiment, locomotor activity in neurologically intact rats was used. Rapid (5-16 sec) intravenous infusions of cocaine induced robust psychomotor sensitization at all doses tested (0.5-2.0 mg/kg). Treatments given over 25 sec failed to induce sensitization at all doses tested. Treatments given over 50 or 100 sec induced sensitization only at the highest dose tested. Thus, the rate of intravenous cocaine delivery has profound effects on the ability of cocaine to induce psychomotor sensitization. This suggests that the temporal dynamics of drug delivery to the brain is a critical factor in the ability of cocaine to induce forms of neuronal plasticity that may contribute to addiction.

Animals↗
PubMed2002

The ability of amphetamine to evoke arc (Arg 3.1) mRNA expression in the caudate, nucleus accumbens and neocortex is modulated by environmental context.

The ability of amphetamine or cocaine to induce the expression of c-fos mRNA in a number of brain regions is greatly enhanced when these drugs are administered in a distinct and relatively novel environment, relative to when they are given in the home cage. The purpose of this study was to determine if environmental context has a similar effect on the ability of amphetamine to induce the expression of arc (also known as Arg 3.1), an "effector" immediate early gene (IEG) thought to play a direct role in cellular plasticity. Rats were administered either saline or amphetamine (0.5 mg/kg, i.v.), in their home cage or in a distinct test environment. Fifty minutes later, they were decapitated and their brains processed for in situ hybridization histochemistry. In the prefrontal cortex, caudate-putamen and core of the nucleus accumbens, amphetamine significantly increased arc mRNA expression under both conditions, but the level of expression was significantly enhanced when amphetamine was given in a distinct environment. In the shell of the nucleus accumbens amphetamine significantly increased the expression of arc mRNA only when it was administered in the distinct environment. Thus, the ability of amphetamine to induce the expression of arc varies as a function of the environmental context in which it is administered. This could contribute to the ability of environmental context to modulate forms of drug experience-dependent neuroplasticity, including behavioral sensitization.

Amphetamine↗
PubMed2002

Memory processes governing amphetamine-induced psychomotor sensitization.

We investigated how, under certain circumstances, the expression of psychomotor sensitization comes to be context-specific. Rats that had previously sustained 6-hydroxydopamine-induced unilateral dopamine depletion received repeated injections of d-amphetamine (AMPH) or saline in group-specific environments, and rotational behavior was measured as an index of psychomotor activation. Following these treatments some groups were given electroconvulsive shock (ECS), when memories of the drug experience were reactivated (and therefore vulnerable to disruption), in order to produce retrograde amnesia. Animals given an AMPH challenge in the environment in which they received drug treatments (Paired) expressed robust sensitization. Animals given an AMPH challenge in a context that was never paired with drug administration (Unpaired) did not express sensitization. A saline challenge in the AMPH paired context produced a conditioned rotational response (CR). ECS had no effect in Control animals, no effect on the expression of sensitization in Paired animals, and no effect on the expression of the CR in Paired animals. However, ECS did affect Unpaired groups: unlike Unpaired animals given sham ECS, Unpaired animals given ECS expressed robust sensitization. Thus, without ECS, the expression of sensitization must have been suppressed in the Unpaired animals (who had the same drug history as Paired animals), and ECS released this otherwise suppressed sensitization. Based on these and other findings, we propose that three memory mechanisms regulate context-specificity of AMPH sensitization: (1) Repeated drug administration induces sensitization of the neural substrate that mediates the unconditional response (UR) to the drug, a form of non-associative learning; (2) An inhibitory process can block the expression of neural sensitization in contexts where the drug is not expected, a process we speculate may involve a form of inhibitory occasion-setting; (3) An excitatory conditioned response (CR) can amplify the sensitized response in a context where the drug is expected. It is suggested that the ability of drug-associated contexts to modulate the expression of neural sensitization via occasion-setting may combine with the ability of a drug-associated context to produce conditioned responses, together providing powerful associative control over not only behavioral sensitization, but in addicts, over craving and relapse.

Amphetamine↗