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1.  Prefrontal cortical–striatal dopamine receptor mRNA expression predicts distinct forms of impulsivity 
The European journal of neuroscience  2013;37(11):1779-1788.
Variation in dopamine receptor levels has been associated with different facets of impulsivity. To further delineate the neural substrates underlying impulsive action (inability to withhold a prepotent motor response) and impulsive choice (delay aversion), we characterised rats in the Differential Reinforcement of Low Rates of Responding task and a delay discounting task. We also measured performance on an effort-based discounting task. We then assessed D1 and D2 dopamine receptor mRNA expression in subregions of the prefrontal cortex and nucleus accumbens using in situ hybridisation, and compared these data with behavioral performance. Expression of D1 and D2 receptor mRNA in distinct brain regions was predictive of impulsive action. A dissociation within the nucleus accumbens was observed between subregions and receptor subtypes; higher D1 mRNA expression in the shell predicted greater impulsive action, whereas lower D2 mRNA expression in the core predicted greater impulsive action. We also observed a negative correlation between impulsive action and D2 mRNA expression in the prelimbic cortex. Interestingly, a similar relationship was present between impulsive choice and prelimbic cortex D2 mRNA, despite the fact that behavioral indices of impulsive action and impulsive choice were uncorrelated. Finally, we found that both high D1 mRNA expression in the insular cortex and low D2 mRNA expression in the infralimbic cortex were associated with willingness to exert effort for rewards. Notably, dopamine receptor mRNA in these regions was not associated with either facet of impulsivity. The data presented here provide novel molecular and neuroanatomical distinctions between different forms of impulsivity, as well as effort-based decision-making.
PMCID: PMC3973541  PMID: 23510331
delay discounting; effort discounting; impulsive action; impulsive choice; rat
2.  α4β2* and α7 Nicotinic Acetylcholine Receptor Binding Predicts Choice Preference in Two Cost Benefit Decision Making Tasks 
Neuroscience  2012;230:121-131.
Nicotinic receptors have been linked to a wide range of cognitive and behavioral functions, but surprisingly little is known about their involvement in cost benefit decision making. The goal of these experiments was to determine how nicotinic acetylcholine receptor (nAChR) expression is related to two forms of cost benefit decision making. Male Long Evans rats were tested in probability and delay discounting tasks, which required discrete trial choices between a small reward and a large reward associated with varying probabilities of omission and varying delays to reward delivery, respectively. Following testing, radioligand binding to α4β2* and α7 nAChR subtypes in brain regions implicated in cost benefit decision making was examined. Significant linear relationships were observed between choice of the large delayed reward in the delay discounting task and α4β2* receptor binding in both dorsal and ventral hippocampus. Additionally, trends were found suggesting that choice of the large costly reward in both discounting tasks was inversely related to α4β2* receptor binding in the medial prefrontal cortex and nucleus accumbens shell. Similar, trends suggested that choice of the large delayed reward in the delay discounting task was inversely related to α4β2* receptor binding in the orbitofrontal cortex, nucleus accumbens core, and basolateral amygdala, as well as to α7 receptor binding in basolateral amygdala. These data suggest that nAChRs (particularly α4β2*) play both unique and common roles in decisions that require consideration of different types of reward costs.
PMCID: PMC3545051  PMID: 23159316
delay discounting; probability discounting; nicotinic receptor; acetylcholine; rat; impulsivity
3.  Effects of acute administration of nicotinic and muscarinic cholinergic agonists and antagonists on performance in different cost–benefit decision making tasks in rats 
Psychopharmacology  2012;224(4):489-499.
Alterations in cost–benefit decision making accompany numerous neuropsychiatric conditions, including schizophrenia, attention deficit hyperactivity disorder, and addiction. Central cholinergic systems have been linked to the etiology and/or treatment of many of these conditions, but little is known about the role of cholinergic signaling in cost–benefit decision making.
The goal of these experiments was to determine how cholinergic signaling is involved in cost–benefit decision making, using a behavioral pharmacological approach.
Male Long-Evans rats were trained in either “probability discounting” or “delay discounting” tasks, in which rats made discrete-trial choices between a small food reward and a large food reward associated with either varying probabilities of omission or varying delays to delivery, respectively. The effects of acute administration of different doses of nicotinic and muscarinic acetylcholine receptor agonists and antagonists were assessed in each task.
In the probability discounting task, acute nicotine administration (1.0 mg/kg) significantly increased choice of the large risky reward, and control experiments suggested that this was due to robust nicotine-induced impairments in behavioral flexibility. In the delay discounting task, the muscarinic antagonists scopolamine (0.03, 0.1, and 0.3 mg/kg) and atropine (0.3 mg/kg) both significantly increased choice of the small immediate reward. Neither mecamylamine nor oxotremorine produced reliable effects on either of the decision making tasks.
These data suggest that cholinergic receptors play multiple roles in decision making contexts which include consideration of reward delay or probability. These roles should be considered when targeting these receptors for therapeutic purposes.
PMCID: PMC3508195  PMID: 22760484
Cholinergic; Nicotinic; Muscarinic; Delay discounting; Probability discounting; Impulsivity; Risk; Perseveration
4.  Blockade of GABA(B) Receptors Completely Reverses Age-related Learning Impairment 
Neuroscience  2009;164(3):941-947.
Impaired cognitive functions are well-described in the aging process. GABA(B) antagonists can facilitate learning and memory in young subjects, but these agents have not been well-characterized in aging. Here we show a complete reversal of olfactory discrimination learning deficits in cognitively-impaired aged Fischer 344 rats using the GABA(B) antagonist CGP55845, such that drug treatment restored performance to that on par with young and cognitively-unimpaired aged subjects. There was no evidence that this improved learning was due to enhanced olfactory detection abilities produced by the drug. These results highlight the potential of targeting GABA(B) receptors to ameliorate age-related cognitive deficits and demonstrate the utility of olfactory discrimination learning as a preclinical model for testing novel therapies to improve cognitive functions in aging.
PMCID: PMC2874897  PMID: 19723562
CGP55845; aging; GABA(B) receptor; cognitive enhancement; odor; learning
5.  GABAB receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats 
Neurobiology of Aging  2011;33(6):1124.e1-1124.e12.
GABAB receptors (GABABRs) have been linked to a wide range of physiological and cognitive processes and are of interest for treating a number of neurodegenerative and psychiatric disorders. As many of these diseases are associated with advanced age, it is important to understand how the normal aging process impacts GABABR expression and signaling. Thus, we investigated GABABR expression and function in the prefrontal cortex (PFC) and hippocampus of young and aged rats characterized in a spatial learning task. Baclofen-stimulated GTP-binding and GABABR1 and GABABR2 proteins were reduced in the PFC of aged rats but these reductions were not associated with spatial learning abilities. In contrast, hippocampal GTP-binding was comparable between young and aged rats but reduced hippocampal GABABR1 expression was observed in aged rats with spatial learning impairment. These data demonstrate marked regional differences in GABABR complexes in the adult and aged brain and could have implications for both understanding the role of GABAergic processes in normal brain function and the development of putative interventions that target this system.
PMCID: PMC3310948  PMID: 22169202
Aging; Baclofen; Spatial learning; GABABR; PFC; Memory
6.  Altered spatial learning and delay discounting in a rat model of human third trimester binge ethanol exposure 
Behavioural Pharmacology  2012;23(1):54-65.
Ethanol exposure during perinatal development can cause cognitive abnormalities including difficulties in learning, attention, and memory, as well as heightened impulsivity. The purpose of this study was to assess performance in spatial learning and impulsive choice tasks in rats subjected to an intragastric intubation model of binge ethanol exposure during human third trimester-equivalent brain development. Male and female Sprague–Dawley rat pups were intubated with ethanol (5.25 g/kg/day) on postnatal days 4–9. At adolescence (between postnatal days 35–38), these rats and sham intubated within-litter controls were trained in both spatial and cued versions of the Morris water maze. A subset of the male rats was subsequently tested on a delay-discounting task to assess impulsive choice. Ethanol-exposed rats were spatially impaired relative to controls, but performed comparably to controls on the cued version of the water maze. Ethanol-exposed rats also showed greater preference for large delayed rewards on the delay discounting task, but no evidence for altered reward sensitivity or perseverative behavior. These data demonstrate that early postnatal intermittent binge-like ethanol exposure has prolonged, detrimental, but selective effects on cognition, suggesting that even relatively brief ethanol exposure late in human pregnancy can be deleterious for cognitive function.
PMCID: PMC3303859  PMID: 22129556
alcohol; binge ethanol exposure; delay discounting; hippocampus; impulsivity; Morris water maze; rat; spatial learning
7.  Brain-derived neurotrophic factor (BDNF) promotes adaptive plasticity within the spinal cord and mediates the beneficial effects of controllable stimulation 
Neuroscience  2011;200C:74-90.
Brain-derived neurotrophic factor (BDNF) has been characterized as a potent modulator of neural plasticity in both the brain and spinal cord. The present experiments use an in vivo model system to demonstrate that training with controllable stimulation increases spinal BDNF expression and engages a BDNF-dependent process that promotes adaptive plasticity.
Spinally transected rats administered legshock whenever one hindlimb is extended (controllable stimulation) exhibit a progressive increase in flexion duration. This simple form of response-outcome (instrumental) learning is not observed when shock is given independent of leg position (uncontrollable stimulation). Uncontrollable electrical stimulation also induces a lasting effect that impairs learning for up to 48 hrs. Training with controllable shock can counter the adverse consequences of uncontrollable stimulation, to both prevent and reverse the learning deficit. Here it is shown that the protective and restorative effect of instrumental training depends on BDNF.
Cellular assays showed that controllable stimulation increased BDNF mRNA expression and protein within the lumbar spinal cord. These changes were associated with an increase in the BDNF receptor TrkB protein within the dorsal horn. Evidence is then presented that these changes play a functional role in vivo. Application of a BDNF inhibitor (TrkB-IgG) blocked the protective effect of instrumental training. Direct (intrathecal) application of BDNF substituted for instrumental training to block both the induction and expression of the learning deficit. Uncontrollable stimulation also induced an increase in mechanical reactivity (allodynia) and this too was prevented by BDNF. TrkB-IgG blocked the restorative effect of instrumental training and intrathecal BDNF substituted for training to reverse the deficit. Taken together, these findings outline a critical role for BDNF in mediating the beneficial effects of controllable stimulation on spinal plasticity.
PMCID: PMC3249495  PMID: 22056599
Brain-derived neurotrophic factor (BDNF); spinal cord; plasticity; instrumental learning
8.  Dopaminergic Modulation of Risky Decision-Making 
The Journal of Neuroscience  2011;31(48):17460-17470.
Many psychiatric disorders are characterized by abnormal risky decision-making and dysregulated dopamine receptor expression. The current study was designed to determine how different dopamine receptor subtypes modulate risk-taking in young adult rats, using a “Risky Decision-making Task” that involves choices between small “safe” rewards and large “risky” rewards accompanied by adverse consequences. Rats showed considerable, stable individual differences in risk preference in the task, which were not related to multiple measures of reward motivation, anxiety, or pain sensitivity. Systemic activation of D2-like receptors robustly attenuated risk-taking, whereas drugs acting on D1-like receptors had no effect. Systemic amphetamine also reduced risk-taking, an effect which was attenuated by D2-like (but not D1-like) receptor blockade. Dopamine receptor mRNA expression was evaluated in a separate cohort of drug-naive rats characterized in the task. D1 mRNA expression in both nucleus accumbens shell and insular cortex was positively associated with risk-taking, while D2 mRNA expression in orbitofrontal and medial prefrontal cortex predicted risk preference in opposing nonlinear patterns. Additionally, lower levels of D2 mRNA in dorsal striatum were associated with greater risk-taking. These data strongly implicate dopamine signaling in prefrontal corticalstriatal circuitry in modulating decision-making processes involving integration of reward information with risks of adverse consequences.
PMCID: PMC3307370  PMID: 22131407
9.  Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies 
Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable.
PMCID: PMC3218805  PMID: 21943025
10.  Challenges and opportunities for characterizing cognitive aging across species 
The gradual decline of cognitive ability with age, even in the absence of overt brain disease, is a growing problem. Although cognitive aging is a common and feared accompaniment of the aging process, its underlying mechanisms are not well understood and there are no highly effective means to prevent it. Additional research on cognitive aging is sorely needed, and methods that enable ready translation between human subjects and animal models stand to provide the most benefit. Here and in the six companion pieces in this special issue, we discuss a variety of challenges and opportunities for studying cognitive aging across species. We identify tests of associative memory, recognition memory, spatial and contextual memory, and working memory and executive function as cognitive domains that are age-sensitive and amenable to testing with parallel means in both humans and animal models. We summarize some of the important challenges in using animal models to test cognition. We describe unique opportunities to study cognitive aging in human subjects, such as those provided by recent large-scale initiatives to characterize cognition in large groups of subjects across the lifespan. Finally, we highlight some of the challenges of studying cognitive aging in human subjects.
PMCID: PMC3439634  PMID: 22988434
cognition; aging; memory; human; animal models
11.  Characterizing cognitive aging of spatial and contextual memory in animal models 
Episodic memory, especially memory for contextual or spatial information, is particularly vulnerable to age-related decline in humans and animal models of aging. The continuing improvement of virtual environment technology for testing humans signifies that widely used procedures employed in the animal literature for examining spatial memory could be developed for examining age-related cognitive decline in humans. The current review examines cross species considerations for implementing these tasks and translating findings across different levels of analysis. The specificity of brain systems as well as gaps in linking human and animal laboratory models is discussed.
PMCID: PMC3439636  PMID: 22988436
spatial; contextual; memory; aging; hippocampus
12.  Characterizing cognitive aging of working memory and executive function in animal models 
Executive functions supported by prefrontal cortical (PFC) systems provide essential control and planning mechanisms to guide goal-directed behavior. As such, age-related alterations in executive functions can mediate profound and widespread deficits on a diverse array of neurocognitive processes. Many of the critical neuroanatomical and functional characteristics of prefrontal cortex are preserved in rodents, allowing for meaningful cross species comparisons relevant to the study of cognitive aging. In particular, as rodents lend themselves to genetic, cellular and biochemical approaches, rodent models of executive function stand to significantly contribute to our understanding of the critical neurobiological mechanisms that mediate decline of executive processes across the lifespan. Moreover, rodent analogs of executive functions that decline in human aging represent an essential component of a targeted, rational approach for developing and testing effective treatment and prevention therapies for age-related cognitive decline. This paper reviews behavioral approaches used to study executive function in rodents, with a focus on those assays that share a foundation in the psychological and neuroanatomical constructs important for human aging. A particular emphasis is placed on behavioral approaches used to assess working memory and cognitive flexibility, which are sensitive to decline with age across species and for which strong rodent models currently exist. In addition, other approaches in rodent behavior that have potential for providing analogs to functions that reliably decline to human aging (e.g., information processing speed) are discussed.
PMCID: PMC3439637  PMID: 22988438
aged; cognitive flexibility; delayed match-to-place; prefrontal cortex; rat; rodents; set-shifting; water maze
13.  Characterizing cognitive aging in humans with links to animal models 
With the population of older adults expected to grow rapidly over the next two decades, it has become increasingly important to advance research efforts to elucidate the mechanisms associated with cognitive aging, with the ultimate goal of developing effective interventions and prevention therapies. Although there has been a vast research literature on the use of cognitive tests to evaluate the effects of aging and age-related neurodegenerative disease, the need for a set of standardized measures to characterize the cognitive profiles specific to healthy aging has been widely recognized. Here we present a review of selected methods and approaches that have been applied in human research studies to evaluate the effects of aging on cognition, including executive function, memory, processing speed, language, and visuospatial function. The effects of healthy aging on each of these cognitive domains are discussed with examples from cognitive/experimental and clinical/neuropsychological approaches. Further, we consider those measures that have clear conceptual and methodological links to tasks currently in use for non-human animal studies of aging, as well as those that have the potential for translation to animal aging research. Having a complementary set of measures to assess the cognitive profiles of healthy aging across species provides a unique opportunity to enhance research efforts for cross-sectional, longitudinal, and intervention studies of cognitive aging. Taking a cross-species, translational approach will help to advance cognitive aging research, leading to a greater understanding of associated neurobiological mechanisms with the potential for developing effective interventions and prevention therapies for age-related cognitive decline.
PMCID: PMC3439638  PMID: 22988439
aging; cognition; memory; executive function; processing speed; visuospatial function; language
14.  Risk, Reward, and Decision-Making in a Rodent Model of Cognitive Aging 
Impaired decision-making in aging can directly impact factors (financial security, health care) that are critical to maintaining quality of life and independence at advanced ages. Naturalistic rodent models mimic human aging in other cognitive domains, and afford the opportunity to parse the effects of age on discrete aspects of decision-making in a manner relatively uncontaminated by experiential factors. Young adult (5–7 months) and aged (23–25 months) male F344 rats were trained on a probability discounting task in which they made discrete-trial choices between a small certain reward (one food pellet) and a large but uncertain reward (two food pellets with varying probabilities of delivery ranging from 100 to 0%). Young rats chose the large reward when it was associated with a high probability of delivery and shifted to the small but certain reward as probability of the large reward decreased. As a group, aged rats performed comparably to young, but there was significantly greater variance among aged rats. One subgroup of aged rats showed strong preference for the small certain reward. This preference was maintained under conditions in which large reward delivery was also certain, suggesting decreased sensitivity to reward magnitude. In contrast, another subgroup of aged rats showed strong preference for the large reward at low probabilities of delivery. Interestingly, this subgroup also showed elevated preference for probabilistic rewards when reward magnitudes were equalized. Previous findings using this same aged study population described strongly attenuated discounting of delayed rewards with age, together suggesting that a subgroup of aged rats may have deficits associated with accounting for reward costs (i.e., delay or probability). These deficits in cost-accounting were dissociable from the age-related differences in sensitivity to reward magnitude, suggesting that aging influences multiple, distinct mechanisms that can impact cost–benefit decision-making.
PMCID: PMC3250056  PMID: 22319463
aged; choice; rats; probability; discounting; reward sensitivity; memory
15.  Long-lasting sensitization of reward-directed behavior by amphetamine 
Behavioural brain research  2009;201(1):74-79.
Exposure to psychostimulant drugs of abuse such as amphetamine can result in long-lasting “sensitization” of reward-directed behavior, such that subjects display enhancements in behavior directed by and toward rewards and reward-predictive cues (i.e. – “incentive sensitization”). The purpose of these experiments was to determine the degree to which such sensitization resulting from chronic amphetamine exposure influences both appetitive and consummatory food-motivated behavior. Adult male Long-Evans rats received daily i.p. injections of d-amphetamine (2.0 mg/kg) or saline vehicle for five consecutive days. This amphetamine exposure regimen produced lasting sensitization to the acute locomotor stimulant effect of the drug. One month after drug exposure rats were tested for instrumental responding (lever pressing) for food reward under various response schedules. Two months after drug exposure, rats were tested for food consumption in a discriminative Pavlovian context-potentiated eating task, involving pairings of one context with food and another context with no food. Amphetamine-exposed rats showed significantly greater instrumental responding for food reward than saline controls, particularly under conditions of high response ratios. In the potentiated eating task, testing under conditions of food satiation revealed that amphetamine-exposed rats ate significantly more than saline controls in the food-paired context. These experiments demonstrate that amphetamine exposure can cause enduring increases in both appetitive and consummatory aspects of natural reward-directed behavior. Such long-lasting incentive sensitization could account in part for the propensity for relapse in drug addiction, as well as for reported enhancements in non-drug reward-related behavior.
PMCID: PMC2680778  PMID: 19428619
Psychostimulant; amphetamine; instrumental responding; sensitization; incentive motivation
16.  Balancing Risk and Reward: A Rat Model of Risky Decision-Making 
We developed a behavioral task in rats to assess the influence of risk of punishment on decision-making. Male Long-Evans rats were given choices between pressing a lever to obtain a small, “safe” food reward and a large food reward associated with risk of punishment (footshock). Each test session consisted of 5 blocks of 10 choice trials, with punishment risk increasing with each consecutive block (0, 25, 50, 75, 100%). Preference for the large, “risky” reward declined with both increased probability and increased magnitude of punishment, and reward choice was not affected by the level of satiation or the order of risk presentation. Performance in this risky decision-making task was correlated with the degree to which the rats discounted the value of probabilistic rewards, but not delayed rewards. Finally, the acute effects of different doses of amphetamine and cocaine on risky decision-making were assessed. Systemic amphetamine administration caused a dose-dependent decrease in choice of the large risky reward (i.e. – it made rats more risk-averse). Cocaine did not cause a shift in reward choice, but instead impaired rats’ sensitivity to changes in punishment risk. These results should prove useful for investigating neuropsychiatric disorders in which risk taking is a prominent feature, such as attention deficit/hyperactivity disorder and addiction.
PMCID: PMC2726909  PMID: 19440192
risk; decision-making; choice; reward; punishment; amphetamine; cocaine
17.  Long-term effects of prior cocaine exposure on Morris water maze performance 
Cocaine addiction is associated with long-term cognitive alterations including deficits on tests of declarative/spatial learning and memory. To determine the extent to which cocaine exposure plays a causative role in these deficits, adult male Long-Evans rats were given daily injections of cocaine (30 mg/kg/day × 14 days) or saline vehicle. Three months later, rats were trained for 6 sessions on a Morris water maze protocol adapted from Gallagher et al. (1993). Rats given prior cocaine exposure performed similarly to controls on training trials, but searched farther from the platform location on probe trials interpolated throughout the training sessions and showed increased thigmotaxis. The results demonstrate that a regimen of cocaine exposure can impair Morris water maze performance as long as 3 months after exposure. Although the impairments were not consistent with major deficits in spatial learning and memory, they may have resulted from cocaine-induced increases in stress responsiveness and/or anxiety. Increased stress and anxiety would be expected to increase thigmotaxis as well as cause impairments in searching for the platform location, possibly through actions on ventral striatal dopamine signaling.
PMCID: PMC2258220  PMID: 17904876
Cocaine; Psychostimulant; Morris water maze; Learning; Stress; Anxiety

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