Alicia Izquierdo

Brief Uncontrollable Stress Causes Dendritic Retraction in Infralimbic Cortex and Resistance to Fear Extinction in Mice

Extinction of conditioned fear responses is an active learning process resulting from the repeated presentation of a conditioned stimulus in the absence of the unconditioned aversive stimulus. Recent research implicates the medial prefrontal cortex (mPFC) in the mediation of fear extinction in rodents and the pathophysiology of posttraumatic stress disorder. However, there is currently little understanding of precisely how stress can impact fear extinction and the neural circuitry subserving this behavior. The present study examined the effects of brief exposure to an uncontrollable stressor on (1) fear conditioning and fear extinction, and (2) dendritic morphology of pyramidal neurons in the infralimbic (IL) and prelimbic (PL) regions of the mPFC in mice. Exposure to three episodes of stress ending 24 h before fear conditioning significantly attenuated the rate of cued fear extinction relative to nonstressed controls, but did not affect fear conditioning or cue or context recall. Analysis of Golgi-stained neurons showed that one or three exposures to daily swim stress caused significant retraction of terminal branches of apical, but not basilar, dendrites of IL neurons. In contrast, PL neuronal morphology was unaltered by stress. These data demonstrate that IL, but not PL, neurons are highly sensitive to even brief exposure to stress, and that this same form of stress impairs fear extinction. Present findings suggest that trauma may compromise the functional integrity of the mPFC with implications for the pathophysiology of certain neuropsychiatric disorders.

Impaired Stress-Coping and Fear Extinction and Abnormal Corticolimbic Morphology in Serotonin Transporter Knock-Out Mice

A lesser-expressing form of the human 5-HT transporter (5-HTT) gene has been associated with increased fear and anxiety and vulnerability to the effects of stress. These phenotypic abnormalities are linked to functional and anatomical disturbances in a neural pathway connecting the prefrontal cortex (PFC) and amygdala. Likewise, rodent and nonhuman primate studies indicate a major role for PFC and amygdala in the mediation of fear- and stress-related behaviors. We used a 5-HTT knock-out (KO) mouse to examine the effects of genetically driven loss of 5-HTT function for the following: (1) depression-related behavior in response to repeated stress, and pavlovian fear conditioning, extinction, and extinction recall; and (2) dendritic morphology and spine density of Golgi-stained pyramidal neurons in the infralimbic cortex (IL) and the basolateral amygdala (BLA). 5-HTT KO mice exhibited increased depressive-like immobility after repeated exposure to forced swim stress, compared with wild-type (WT) controls. Whereas fear conditioning and fear extinction was normal, 5-HTT KO mice exhibited a significant deficit in extinction recall. The apical dendritic branches of IL pyramidal neurons in 5-HTT KO mice were significantly increased in length relative to WT mice. Pyramidal neurons in BLA had normal dendritic morphology but significantly greater spine density in 5-HT KO mice compared with WT mice. Together, the present findings demonstrate a specific phenotypic profile of fear- and stress-related deficits in 5-HTT KO mice, accompanied by morphological abnormalities in two key neural loci. These data provide insight into the behavioral sequelae of loss of 5-HTT gene function and identify potential neural substrates underlying these phenotypes.

Reversal learning as a measure of impulsive and compulsive behavior in addictions

BackgroundOur ability to measure the cognitive components of complex decision-making across species has greatly facilitated our understanding of its neurobiological mechanisms. One task in particular, reversal learning, has proven valuable in assessing the inhibitory processes that are central to executive control. Reversal learning measures the ability to actively suppress reward-related responding and to disengage from ongoing behavior, phenomena that are biologically and descriptively related to impulsivity and compulsivity. Consequently, reversal learning could index vulnerability for disorders characterized by impulsivity such as proclivity for initial substance abuse as well as the compulsive aspects of dependence.ObjectiveThough we describe common variants and similar tasks, we pay particular attention to discrimination reversal learning, its supporting neural circuitry, neuropharmacology and genetic determinants. We also review the utility of this task in measuring impulsivity and compulsivity in addictions.MethodsWe restrict our review to instrumental, reward-related reversal learning studies as they are most germane to addiction.ConclusionThe research reviewed here suggests that discrimination reversal learning may be used as a diagnostic tool for investigating the neural mechanisms that mediate impulsive and compulsive aspects of pathological reward-seeking and -taking behaviors. Two interrelated mechanisms are posited for the neuroadaptations in addiction that often translate to poor reversal learning: frontocorticostriatal circuitry dysregulation and poor dopamine (D2 receptor) modulation of this circuitry. These data suggest new approaches to targeting inhibitory control mechanisms in addictions.

Pharmacological or Genetic Inactivation of the Serotonin Transporter Improves Reversal Learning in Mice

Growing evidence supports a major contribution of cortical serotonin (5-hydroxytryptamine, 5-HT) to the modulation of cognitive flexibility and the cognitive inflexibility evident in neuropsychiatric disorders. The precise role of 5-HT and the influence of 5-HT gene variation in mediating this process is not fully understood. Using a touch screen-based operant system, we assessed reversal of a pairwise visual discrimination as an assay for cognitive flexibility. Effects of constitutive genetic or pharmacological inactivation of the 5-HT transporter (5-HTT) on reversal were examined by testing 5-HTT null mice and chronic fluoxetine-treated C57BL/6J mice, respectively. Effects of constitutive genetic loss or acute pharmacological depletion of 5-HT were assessed by testing Pet-1 null mice and para-chlorophenylalanine (PCPA)-treated C57BL/6J mice, respectively. Fluoxetine-treated C57BL/6J mice made fewer errors than controls during the early phase of reversal when perseverative behavior is relatively high. 5-HTT null mice made fewer errors than controls in completing the reversal task. However, reversal in Pet-1 null and PCPA-treated C57BL/6J mice was not different from controls. These data further support an important role for 5-HT in modulating reversal learning and provide novel evidence that inactivating the 5-HTT improves this process. These findings could have important implications for understanding and treating cognitive inflexibility in neuropsychiatric disease.

Orbitofrontal Cortex and Amygdala Contributions to Affect and Action in Primates

Abstract:  The amygdala and orbitofrontal cortex (OFC) work together as part of the neural circuitry guiding goal‐directed behavior. This chapter explores the way in which the amygdala and OFC contribute to emotion and reward processing in macaque monkeys, taking into account recent methodological and conceptual advances. Although direct functional interaction of the amygdala and OFC is necessary for some types of stimulus–reward associations, it is not necessary for others. Both regions contribute to the expression of defensive responses to a potential predator. Contrary to the prevailing view, the amygdala and OFC make distinct contributions to emotional responses and reward processing.

Selective bilateral amygdala lesions in rhesus monkeys fail to disrupt object reversal learning

Neuropsychological studies in nonhuman primates have led to the view that the amygdala plays an essential role in stimulus–reward association. The main evidence in support of this idea is that bilateral aspirative or radiofrequency lesions of the amygdala yield severe impairments on object reversal learning, a task that assesses the ability to shift choices of objects based on the presence or absence of food reward (i.e., reward contingency). The behavioral effects of different lesion techniques, however, can vary. The present study therefore evaluated the effects of selective, excitotoxic lesions of the amygdala in rhesus monkeys on object reversal learning. For comparison, we tested the same monkeys on a task known to be sensitive to amygdala damage, the reinforcer devaluation task. Contrary to previous results based on less selective lesion techniques, monkeys with complete excitotoxic amygdala lesions performed object reversal learning as quickly as controls. As predicted, however, the same operated monkeys were impaired in making object choices after devaluation of the associated food reinforcer. The results suggest two conclusions. First, the results demonstrate that the amygdala makes a selective contribution to stimulus–reward association; the amygdala is critical for guiding object choices after changes in reward value but not after changes in reward contingency. Second, the results implicate a critical contribution to object reversal learning of structures nearby the amygdala, perhaps the subjacent rhinal cortex.

Opposing effects of amygdala and orbital prefrontal cortex lesions on the extinction of instrumental responding in macaque monkeys

Extinction is a well‐known behavioural phenomenon that allows organisms to respond flexibly to a changing environment. Although recent work implicates the amygdala and orbital prefrontal cortex (PFo) in extinction of Pavlovian conditioned fear and aversion, much less is known about the neural bases of instrumental extinction. To explore the contribution of the macaque amygdala to flexible responding in the face of changing reward contingency, we tested the effects of selective, excitotoxic lesions of the amygdala on extinction of an instrumental response. For comparison, we evaluated the effects of ablation of PFo on the same task. Amygdala lesions facilitated the extinction of instrumental responses, whereas lesions of PFo had the opposite effect.

Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice.

Mice are uniquely suited as experimental subjects for various approaches to the study of the molecular and genetic basis of behavior, and there has been a corresponding explosion in the use of mice in behavioral neuroscience. Rats and monkeys, however, remain the preferred species for high-order cognitive models largely due to the unavailability of valid, reliable and translatable endpoint measures of behavior in the mouse. Here we present further development and validation of a touchscreen-based operant method for measuring cognition that is comparable to methods used in other species and human patients. C57BL/6J mice were found to show good performance on visual discrimination and reversal learning using this method. Demonstrating the sensitivity of the paradigm to genetic factors, C57BL/6J and DBA/2J mice exhibited marked differences in discrimination and reversal learning. Systemic treatment with the selective D1-like agonist, SKF81297, produced an impairment in the early phase of reversal learning, but did not alter visual discrimination, in C57BL/6J mice. The same treatment impaired spatial working memory on the T-maze delayed alternation task, but did not alter control measures of behavior including motivation and locomotor activity. These data demonstrate the sensitivity of visual discrimination and reversal learning measured by this method to genetic factors and pharmacological challenge, and thereby provide an extension and further validation of the method for measuring cognition in mice. When combined with emerging molecular techniques uniquely suited to this species such as genetic engineering and RNA modification this paradigm could provide a powerful new tool for behavioral neuroscience.

Reversal-Specific Learning Impairments After a Binge Regimen of Methamphetamine in Rats: Possible Involvement of Striatal Dopamine

A growing body of evidence indicates that protracted use of methamphetamine (mAMPH) causes long-term impairments in cognitive function in humans. Aside from the widely reported problems with attention, mAMPH users exhibit learning and memory deficits, particularly on tasks requiring response control. Although binge mAMPH administration to animals results in cognitive deficits, few studies have attempted to test behavioral flexibility in animals after mAMPH exposure. The aim of this study was to evaluate whether mAMPH would produce impairments in two tasks assessing flexible responding in rats: a touchscreen-based discrimination-reversal learning task and an attentional set shift task (ASST) based on a hallmark test of executive function in humans, the Wisconsin Card Sort. We treated male Long-Evans rats with a regimen of four injections of 2 mg/kg mAMPH (or vehicle) within a single day, a dosing regimen shown earlier to produce object recognition impairments. We then tested them on (1) reversal learning after pretreatment discrimination learning or (2) the ASST. Early reversal learning accuracy was impaired in mAMPH-treated rats. MAMPH pretreatment also selectively impaired reversal performance during ASST testing, leaving set-shifting performance intact. Postmortem analysis of [125I]RTI-55 binding revealed small (10–20%) but significant reductions in striatal dopamine transporters produced by this mAMPH regimen. Together, these results lend new information to the growing field documenting impaired cognition after mAMPH exposure, and constitute a rat model of the widely reported decision-making deficits resulting from mAMPH abuse seen in humans.

The basolateral amygdala in reward learning and addiction

Sophisticated behavioral paradigms partnered with the emergence of increasingly selective techniques to target the basolateral amygdala (BLA) have resulted in an enhanced understanding of the role of this nucleus in learning and using reward information. Due to the wide variety of behavioral approaches many questions remain on the circumscribed role of BLA in appetitive behavior. In this review, we integrate conclusions of BLA function in reward-related behavior using traditional interference techniques (lesion, pharmacological inactivation) with those using newer methodological approaches in experimental animals that allow in vivo manipulation of cell type-specific populations and neural recordings. Secondly, from a review of appetitive behavioral tasks in rodents and monkeys and recent computational models of reward procurement, we derive evidence for BLA as a neural integrator of reward value, history, and cost parameters. Taken together, BLA codes specific and temporally dynamic outcome representations in a distributed network to orchestrate adaptive responses. We provide evidence that experiences with opiates and psychostimulants alter these outcome representations in BLA, resulting in long-term modified action.