Biomedical subjects

R Andrew Chambers

Publications and source records attributed to R Andrew Chambers.

11 recordsLinked to original sources

PubMed2007

Network modeling of adult neurogenesis: shifting rates of neuronal turnover optimally gears network learning according to novelty gradient.

Apoptotic and neurogenic events in the adult hippocampus are hypothesized to play a role in cognitive responses to new contexts. Corticosteroid-mediated stress responses and other neural processes invoked by substantially novel contextual changes may regulate these processes. Using elementary three-layer neural networks that learn by incremental synaptic plasticity, we explored whether the cognitive effects of differential regimens of neuronal turnover depend on the environmental context in terms of the degree of novelty in the new information to be learned. In "adult" networks that had achieved mature synaptic connectivity upon prior learning of the Roman alphabet, imposition of apoptosis/neurogenesis before learning increasingly novel information (alternate Roman < Russian < Hebrew) reveals optimality of informatic cost benefits when rates of turnover are geared in proportion to the degree of novelty. These findings predict that flexible control of rates of apoptosis-neurogenesis within plastic, mature neural systems optimizes learning attributes under varying degrees of contextual change, and that failures in this regulation may define a role for adult hippocampal neurogenesis in novelty- and stress-responsive psychiatric disorders.

Analysis of Variance↗

PubMed2006

Ethanol sensitization in a neurodevelopmental lesion model of schizophrenia in rats.

Substance use disorder comorbidity in schizophrenia may reflect dysfunctional cortical-striatal-limbic circuitry commonly involved in the addiction process and the pathogenesis of schizophrenia. Rats with neonatal ventral hippocampal lesions (NVHL) demonstrate post-adolescent onset of schizophrenia-like symptoms and increased addiction vulnerability in paradigms using cocaine in adulthood. Here, we investigated response profiles of young adult NVHL vs. SHAM rats to ethanol, an addictive drug with many psychopharmacological effects divergent from those of cocaine, in a locomotor sensitization paradigm. Over 15 days of daily injections of saline, low (0.15 g/kg) or high (1.0 g/kg) doses of ethanol, NVHL rats showed stimulatory effects at the low dose compared to saline and high-dose conditions, while SHAM rats showed expected patterns of dose-dependent suppression of locomotor activity. In a challenge session 2 weeks later in which a moderate dose (0.25 g/kg) of ethanol was given to all subjects, NVHL rats with history of prior ethanol exposure showed greater locomotor activity consistent with installment of alcohol-induced sensitization not present in SHAMs. These findings provide further evidence of enhanced short- and long-term responsivity to abused drugs in a neurodevelopmental model of schizophrenia, and may reflect potentiation of common mechanisms of addiction shared between pharmacologically diverse addictive drugs.

Animals↗

PubMed2006

Huntington disease as a dual diagnosis disorder: data from the National Research Roster for Huntington disease patients and families.

Although an extensive literature characterizes a linkage between primary mental illnesses and substance use disorders, a paucity of research exists concerning dual diagnosis phenomena in Huntington disease (HD). Data from the National Research Roster on HD suggest that higher levels of alcohol and cigarette use are associated with greater ratings of psychiatric symptoms and a younger age of HD symptom onset, and that progressive alcohol use after HD symptom onset is linked with worsening psychiatric symptom progression. These findings suggest HD entails dual diagnosis phenomena similar to that identified in patients with primary psychiatric disorders.

Aged, 80 and over↗

PubMed2004

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure.

RATIONALE: Psychostimulant injections in rats have been shown to alter future performance in natural reward conditioning. These effects may represent a persistent impact of drugs on neurocircuits that interface cognitive and motivational processes, which may be further altered in neuropsychiatric conditions that entail increased addiction vulnerability. OBJECTIVE: This study investigated whether a rat model of schizophrenia with cocaine addiction vulnerability shows altered natural reward conditioning with or without prior cocaine exposure. METHODS: Adult rats with SHAM or neonatal ventral hippocampal lesions were given cocaine (15 mg/kg per day for 5 days) or saline injections, followed 7 days later by natural reward-conditioned learning. Over ten daily sessions, water-restricted rats were assessed for durations of head entries into a magazine during random water presentations, a conditioning stimulus phase predictive of the water reward, and an "inappropriate" phase when conditioning stimuli were absent and reward presentation would be delayed. RESULTS: Over repeated sessions, lesioned and SHAM rats showed similar reductions in total magazine entry durations, with similar increases in the allocations of entry times during the water presentation. However, lesioned rats, especially those exposed to cocaine, demonstrated reduced allocations of magazine entry times during the conditioning stimulus phase, and increased allocations during the inappropriate phase. CONCLUSIONS: Intact natural reward motivation accompanied by deficient learning of complex contingencies to guide efficient reward approach may represent a form of impulsivity as an addiction vulnerability trait marker in an animal model of schizophrenia.

Animals↗

PubMed2004

Animal modeling dual diagnosis schizophrenia: sensitization to cocaine in rats with neonatal ventral hippocampal lesions.

BACKGROUND: Increased substance disorder comorbidity in schizophrenia may reflect greater vulnerability to addictive processes because of inherent neurocircuit dysfunction in the schizophrenic brain. METHODS: To further explore this hypothesis, we used neonatal ventral hippocampal lesions (NVHL) as a rat model of schizophrenia and assessed locomotor sensitization to cocaine (15 mg/kg) in adulthood. RESULTS: The NVHL animals showed greater activity in response to an initial cocaine injection compared with sham and saline-treated groups. With daily cocaine injections over 7 days, NVHL rats showed elevated locomotor sensitization curves with greater fluctuations in the intersession changes in activity between days 4 and 7. In a single session 4 weeks later, NVHL compared with SHAM rats showed maintenance of cocaine-associated hyperactivity, as if superimposed on long-term sensitization effects present in both groups. CONCLUSIONS: In a neurodevelopmental model of schizophrenia, the locomotor effects of cocaine were augmented on initial and repeated doses, with emergence of irregularity in sensitization-related changes in activity in the short term and perseverance of augmented effects in the long term. Altered patterns of behavioral sensitization, as a possible correlate of greater addiction vulnerability, can occur as a by-product of neural systems dysfunction responsible for major psychiatric syndromes.

Animals↗

PubMed2004

Locomotor sensitization to cocaine in rats with olfactory bulbectomy.

Olfactory bulbectomy in rats has been suggested as a comprehensive animal model of affective disorders associated with an array of behavioral changes, responsivity to chronic antidepressant treatment, and alterations in limbic structures thought to be critical in the pathophysiology of affective disorders. Recent work showing increased motivational responsivity to amphetamine suggests that olfactory bulbectomy could also be a useful animal model of dual diagnosis disorders. To further investigate this possibility, we studied locomotor activity in olfactory bulbectomized rats 14 days postsurgery in response to novelty and upon acute and repeated injections of cocaine (15/mg/kg) or saline. Consistent with prior studies, lesioned animals showed greater locomotor activity in response to a novel environment and significantly heightened locomotor activation upon initial cocaine exposure. Over 7 days of repeated cocaine injections, lesioned animals also showed a presensitized pattern of activity, with a loss of incremental increases in locomotion observed in control animals. Daily saline injections produced no group differences in pre- or postinjection activity, while cocaine-treated bulbectomized rats demonstrated a decline in their daily preinjection activity. These results suggest that neural alterations caused by olfactory bulbectomy produce altered behavioral response patterns to repeated doses of cocaine, and support the study of olfactory bulbectomy as a useful neurobehavioral model for understanding substance use disorder comorbidity in mental illness.

Animals↗

PubMed2004

Regulation of affect by the lateral septum: implications for neuropsychiatry.

Substantial evidence indicates that the lateral septum (LS) plays a critical role in regulating processes related to mood and motivation. This review presents findings from the basic neuroscience literature and from some clinically oriented research, drawing from behavioral, neuroanatomical, electrophysiological, and molecular studies in support of such a role, and articulates models and hypotheses intended to advance our understanding of these functions. Neuroanatomically, the LS is connected with numerous regions known to regulate affect, such as the hippocampus, amygdala, and hypothalamus. Through its connections with the mesocorticolimbic dopamine system, the LS regulates motivation, both by stimulating the activity of midbrain dopamine neurons and regulating the consequences of this activity on the ventral striatum. Evidence that LS function could impact processes related to schizophrenia and other psychotic spectrum disorders, such as alterations in LS function following administration of antipsychotics and psychotomimetics in animals, will also be presented. The LS can also diminish or enable fear responding when its neural activity is stimulated or inhibited, respectively, perhaps through its projections to the hypothalamus. It also regulates behavioral manifestations of depression, with antidepressants stimulating the activity of LS neurons, and depression-like phenotypes corresponding to blunted activity of LS neurons; serotonin likely plays a key role in modulating these functions by influencing the responsiveness of the LS to hippocampal input. In conclusion, a better understanding of the LS may provide important and useful information in the pursuit of better treatments for a wide range of psychiatric conditions typified by disregulation of affective functions.

Animals↗

PubMed2004

Simulated apoptosis/neurogenesis regulates learning and memory capabilities of adaptive neural networks.

Characterization of neuronal death and neurogenesis in the adult brain of birds, humans, and other mammals raises the possibility that neuronal turnover represents a special form of neuroplasticity associated with stress responses, cognition, and the pathophysiology and treatment of psychiatric disorders. Multilayer neural network models capable of learning alphabetic character representations via incremental synaptic connection strength changes were used to assess additional learning and memory effects incurred by simulation of coordinated apoptotic and neurogenic events in the middle layer. Using a consistent incremental learning capability across all neurons and experimental conditions, increasing the number of middle layer neurons undergoing turnover increased network learning capacity for new information, and increased forgetting of old information. Simulations also showed that specific patterns of neural turnover based on individual neuronal connection characteristics, or the temporal-spatial pattern of neurons chosen for turnover during new learning impacts new learning performance. These simulations predict that apoptotic and neurogenic events could act together to produce specific learning and memory effects beyond those provided by ongoing mechanisms of connection plasticity in neuronal populations. Regulation of rates as well as patterns of neuronal turnover may serve an important function in tuning the informatic properties of plastic networks according to novel informational demands. Analogous regulation in the hippocampus may provide for adaptive cognitive and emotional responses to novel and stressful contexts, or operate suboptimally as a basis for psychiatric disorders. The implications of these elementary simulations for future biological and neural modeling research on apoptosis and neurogenesis are discussed.

Animals↗

PubMed2003

Neurodevelopment, impulsivity, and adolescent gambling.

The prevalence of problem and pathological gambling in adolescence and young adulthood has been found to be two- to fourfold higher than in adulthood. Given that these high rates might predict future increases across all age groups, it is important to explore the causes of the elevated rates of problem and pathological gambling among youths. This article reviews evidence for a neurobiological basis for adolescent vulnerability to problem and pathological gambling behaviors. We propose that a common trait motif of impulsivity might underlie phenomenology of pathological gambling, commonly comorbid psychiatric disorders, and related aspects of adolescent behavior. Recent advances in understanding the brain mechanisms involved in motivation, reward, and decision-making allow a discussion of neural circuitry underlying impulsivity. Emerging data indicate that important neurodevelopmental events during adolescence occur in brain regions associated with motivation and impulsive behavior. We hypothesize that immaturity of frontal cortical and subcortical monoaminergic systems during normal neurodevelopment underlies adolescent impulsivity as a transitional trait-behavior. While these neurodevelopmental processes may confer advantage by promoting a learning drive for optimal adaptation to adult roles, they may also confer an increased vulnerability to addictive behaviors such as problem and pathological gambling. An exploration of the developmental changes in neural circuitry involved in impulse control has significant implications for understanding adolescent behaviors and treating problem and pathological gambling among youths.

Adolescent↗

PubMed2003

Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability.

OBJECTIVE: Epidemiological studies indicate that experimentation with addictive drugs and onset of addictive disorders is primarily concentrated in adolescence and young adulthood. The authors describe basic and clinical data supporting adolescent neurodevelopment as a biologically critical period of greater vulnerability for experimentation with substances and acquisition of substance use disorders. METHOD: The authors reviewed recent literature regarding neurocircuitry underlying motivation, impulsivity, and addiction, with a focus on studies investigating adolescent neurodevelopment. RESULTS: Adolescent neurodevelopment occurs in brain regions associated with motivation, impulsivity, and addiction. Adolescent impulsivity and/or novelty seeking as a transitional trait behavior can be explained in part by maturational changes in frontal cortical and subcortical monoaminergic systems. These developmental processes may advantageously promote learning drives for adaptation to adult roles but may also confer greater vulnerability to the addictive actions of drugs. CONCLUSIONS: An exploration of developmental changes in neurocircuitry involved in impulse control has significant implications for understanding adolescent behavior, addiction vulnerability, and the prevention of addiction in adolescence and adulthood.

Adaptation, Psychological↗

PubMed2002

Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia.

The high prevalence of substance use disorders in schizophrenia relative to the general population and other psychiatric diagnoses could result from developmental neuropathology in hippocampal and cortical structures that underlie schizophrenia. In this study, we tested the effects of neonatal ventral hippocampal lesions on instrumental behavior reinforced by sucrose pellets and intravenous cocaine injections. Lesioned rats acquired sucrose self-administration faster than sham-lesioned rats, but rates of extinction were not altered. Lesioned rats also responded at higher rates during acquisition of cocaine self-administration, and tended to acquire self-administration faster. Higher response rates reflected perseveration of responding during the post-injection "time-out" periods, and a greater incidence of binge-like cocaine intake, which persisted even after cocaine self-administration stabilized. In contrast to sucrose, extinction from cocaine self-administration was prolonged in lesioned rats, and reinstatement of cocaine seeking induced by cocaine priming increased compared with shams. These results suggest that neonatal ventral hippocampal lesions facilitate instrumental learning for both natural and drug rewards, and reduce inhibitory control over cocaine taking while promoting cocaine seeking and relapse after withdrawal. The findings are discussed in terms of possible developmental or direct effects of the lesions, and both positive reinforcement (substance use vulnerability as a primary disease symptom) and negative reinforcement (self-medication) theories of substance use comorbidity in schizophrenia.

Animals↗