Frontal Lobe Contusion in Mice Chronically Impairs Prefrontal-Dependent Behavior

Traumatic brain injury (TBI) is a major cause of chronic disability in the world. Moderate to severe TBI often results in damage to the frontal lobe region and leads to cognitive, emotional, and social behavioral sequelae that negatively affect quality of life. More specifically, TBI patients often develop persistent deficits in social behavior, anxiety, and executive functions such as attention, mental flexibility, and task switching. These deficits are intrinsically associated with prefrontal cortex (PFC) functionality. Currently, there is a lack of analogous, behaviorally characterized TBI models for investigating frontal lobe injuries despite the prevalence of focal contusions to the frontal lobe in TBI patients. We used the controlled cortical impact (CCI) model in mice to generate a frontal lobe contusion and studied behavioral changes associated with PFC function. We found that unilateral frontal lobe contusion in mice produced long-term impairments to social recognition and reversal learning while having only a minor effect on anxiety and completely sparing rule shifting and hippocampal-dependent behavior.     

Operant Procedures for Assessing Behavioral Flexibility in Rats

Executive functions consist of multiple high-level cognitive processes that drive rule generation and behavioral selection. An emergent property of these processes is the ability to adjust behavior in response to changes in one’s environment (i.e., behavioral flexibility). These processes are essential to normal human behavior, and may be disrupted in diverse neuropsychiatric conditions, including schizophrenia, alcoholism, depression, stroke, and Alzheimer’s disease. Understanding of the neurobiology of executive functions has been greatly advanced by the availability of animal tasks for assessing discrete components of behavioral flexibility, particularly strategy shifting and reversal learning. While several types of tasks have been developed, most are non-automated, labor intensive, and allow testing of only one animal at a time. The recent development of automated, operant-based tasks for assessing behavioral flexibility streamlines testing, standardizes stimulus presentation and data recording, and dramatically improves throughput. Here, we describe automated strategy shifting and reversal tasks, using operant chambers controlled by custom written software programs. Using these tasks, we have shown that the medial prefrontal cortex governs strategy shifting but not reversal learning in the rat, similar to the dissociation observed in humans. Moreover, animals with a neonatal hippocampal lesion, a neurodevelopmental model of schizophrenia, are selectively impaired on the strategy shifting task but not the reversal task. The strategy shifting task also allows the identification of separate types of performance errors, each of which is attributable to distinct neural substrates. The availability of these automated tasks, and the evidence supporting the dissociable contributions of separate prefrontal areas, makes them particularly well-suited assays for the investigation of basic neurobiological processes as well as drug discovery and screening in disease models.     

Orexin deficiency modulates cognitive flexibility in a sex-dependent manner

Cognitive flexibility is an important executive function and refers to the ability to adapt behaviors in response to changes in the environment. Of note, many brain disorders are associated with impairments in cognitive flexibility. Several classical neurotransmitter systems including dopamine, acetylcholine and noradrenaline are shown to be important for cognitive flexibility, however, there is not much known about the role of neuropeptides. The neuropeptide orexin, which is brain-widely released by neurons in the lateral hypothalamus, is a major player in maintaining sleep/wake cycle, feeding behavior, arousal, and motivational behavior. Recent studies showed a role of orexin in attention, cognition and stress-induced attenuation of cognitive flexibility by disrupting orexin signaling locally or systemically. However, it is not known so far whether brain-wide reduction or loss of orexin affects cognitive flexibility. We investigated this question by testing male and female orexin-deficient mice in the attentional set shifting task (ASST), an established paradigm of cognitive flexibility. We found that orexin deficiency impaired the intra-dimensional shift phase of the ASST selectively in female homozygous orexin-deficient mice and improved the first reversal learning phase selectively in male homozygous orexin-deficient mice. We also found that these orexin-mediated sex-based modulations of cognitive flexibility were not correlated with trait anxiety, narcoleptic episodes, and reward consumption. Our findings highlight a sexually dimorphic role of orexin in regulating cognitive flexibility and the need for further investigations of sex-specific functions of the orexin circuitry.     

Stochastic Dynamics Underlying Cognitive Stability and Flexibility

Cognitive stability and flexibility are core functions in the successful pursuit of behavioral goals. While there is evidence for a common frontoparietal network underlying both functions and for a key role of dopamine in the modulation of flexible versus stable behavior, the exact neurocomputational mechanisms underlying those executive functions and their adaptation to environmental demands are still unclear. In this work we study the neurocomputational mechanisms underlying cue based task switching (flexibility) and distractor inhibition (stability) in a paradigm specifically designed to probe both functions. We develop a physiologically plausible, explicit model of neural networks that maintain the currently active task rule in working memory and implement the decision process. We simplify the four-choice decision network to a nonlinear drift-diffusion process that we canonically derive from a generic winner-take-all network model. By fitting our model to the behavioral data of individual subjects, we can reproduce their full behavior in terms of decisions and reaction time distributions in baseline as well as distractor inhibition and switch conditions. Furthermore, we predict the individual hemodynamic response timecourse of the rule-representing network and localize it to a frontoparietal network including the inferior frontal junction area and the intraparietal sulcus, using functional magnetic resonance imaging. This refines the understanding of task-switch-related frontoparietal brain activity as reflecting attractor-like working memory representations of task rules. Finally, we estimate the subject-specific stability of the rule-representing attractor states in terms of the minimal action associated with a transition between different rule states in the phase-space of the fitted models. This stability measure correlates with switching-specific thalamocorticostriatal activation, i.e., with a system associated with flexible working memory updating and dopaminergic modulation of cognitive flexibility. These results show that stochastic dynamical systems can implement the basic computations underlying cognitive stability and flexibility and explain neurobiological bases of individual differences.     

The influence of offspring,parity, and oxytocin on cognitive flexibility during the postpartum period

Pregnancy and the postpartum period are times of profound behavioral change including alterations in cognitive function. This has been most often studied using hippocampal-dependent tasks assessing spatial learning and memory. However, less is known about the cognitive effects of motherhood for tasks that rely on areas other than the hippocampus. We have previously shown that postpartum females perform better on the extradimensional phase of an attentional set shifting task, a measure of cognitive flexibility which is dependent on the medial prefrontal cortex (mPFC). The present experiments aimed to extend this work by examining the importance of postpartum stage as well as offspring and parity in driving improved mPFC cognitive function during motherhood. We also examined whether the neuropeptide oxytocin, which plays a role in regulating numerous maternal functions, mediates enhanced cognitive flexibility during motherhood. Our results demonstrate that compared to virgin females, cognitive flexibility is enhanced in mothers regardless of postpartum stage and is not affected by parity since both first (primiparous) and second (biparous) time mothers showed the enhancement. Moreover, we found that improved cognitive flexibility in mothers requires the presence of offspring, as removal of the pups abolished the cognitive enhancement in postpartum females. Lastly, using an oxytocin receptor antagonist, we demonstrate that oxytocin signaling in the mPFC is necessary for the beneficial effects of motherhood on cognitive flexibility. Together, these data provide insights into the temporal, experiential and hormonal factors which regulate mPFC-dependent cognitive function during the postpartum period.     

Getting formal with dopamine and reward

Recent neurophysiological studies reveal that neurons in certain brain structures carry specific signals about past and future rewards. Dopamine neurons display a short-latency, phasic reward signal indicating the difference between actual and predicted rewards. The signal is useful for enhancing neuronal processing and learning behavioral reactions. It is distinctly different from dopamine's tonic enabling of numerous behavioral processes. Neurons in the striatum, frontal cortex, and amygdala also process reward information but provide more differentiated information for identifying and anticipating rewards and organizing goal-directed behavior. The different reward signals have complementary functions, and the optimal use of rewards in voluntary behavior would benefit from interactions between the signals. Addictive psychostimulant drugs may exert their action by amplifying the dopamine reward signal.     

Behavioral and Neuroanatomical Abnormalities in Pleiotrophin Knockout Mice

Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.     

Behavioral and neural analysis of associative learning in the honeybee: a taste from the magic well

Equipped with a mini brain smaller than one cubic millimeter and containing only 950,000 neurons, honeybees could be indeed considered as having rather limited cognitive abilities. However, bees display a rich and interesting behavioral repertoire, in which learning and memory play a fundamental role in the framework of foraging activities. We focus on the question of whether adaptive behavior in honeybees exceeds simple forms of learning and whether the neural mechanisms of complex learning can be unraveled by studying the honeybee brain. Besides elemental forms of learning, in which bees learn specific and univocal links between events in their environment, bees also master different forms of non-elemental learning, including categorization, contextual learning and rule abstraction, both in the visual and in the olfactory domain. Different protocols allow accessing the neural substrates of some of these learning forms and understanding how complex problem solving can be achieved by a relatively simple neural architecture. These results underline the enormous richness of experience-dependent behavior in honeybees, its high flexibility, and the fact that it is possible to formalize and characterize in controlled laboratory protocols basic and higher-order cognitive processing using an insect as a model. This paper is dedicated to the memory of Guillermo ‘Willy’ Zaccardi (1972–2007), disciple and friend beyond time and distance, who will always be remembered with a smile.     

Emotional and cognitive changes during adolescence

Adolescence is a critical period for maturation of neurobiological processes that underlie higher cognitive functions and social and emotional behavior. Recent studies have applied new advances in magnetic resonance imaging to increase understanding of the neurobiological changes that occur during the transition from childhood to early adulthood. Structural imaging data indicate progressive and regressive changes in the relative volumes of specific brain regions, although total brain volume is not significantly altered. The prefrontal cortex matures later than other regions and its development is paralleled by increased abilities in abstract reasoning, attentional shifting, response inhibition and processing speed. Changes in emotional capacity, including improvements in affective modulation and discrimination of emotional cues, are also seen during adolescence. Functional imaging studies using cognitive and affective challenges have shown that frontal cortical networks undergo developmental changes in processing. In summary, brain regions that underlie attention, reward evaluation, affective discrimination, response inhibition and goal-directed behavior undergo structural and functional re-organization throughout late childhood and early adulthood. Evidence from recent imaging studies supports a model by which the frontal cortex adopts an increasingly regulatory role. These neurobiological changes are believed to contribute, in part, to the range in cognitive and affective behavior seen during adolescence.     

Neuroactive steroids: new biomarkers of cognitive aging

Intensive studies in animals established that neuroactive steroids display neuronal actions and influence behavioral functions. We describe here investigations on the role of neuroactive steroids in learning and memory processes during aging and suggest their role as biomarkers of cognitive aging. Our work demonstrated the role of the steroid pregnenolone (PREG) sulfate as a factor underlying an individual’s age-related cognitive decline in animals. As new perspectives of research we argue that knowing whether neuroactive steroids exist as endogenous neuromodulators and modulate physiologically behavioral functions is essential. To this end, a new approach using the sensitive, specific, and accurate quantitative determination of neuroactive steroids by mass spectrometry seems to have potential for examining the role of each steroid in discrete brain areas in learning and memory alterations, as observed during aging.     

Automated Visual Cognitive Tasks for Recording Neural Activity Using a Floor Projection Maze

Neuropsychological tasks used in primates to investigate mechanisms of learning and memory are typically visually guided cognitive tasks. We have developed visual cognitive tasks for rats using the Floor Projection Maze^1,2 that are optimized for visual abilities of rats permitting stronger comparisons of experimental findings with other species.In order to investigate neural correlates of learning and memory, we have integrated electrophysiological recordings into fully automated cognitive tasks on the Floor Projection Maze^1,2. Behavioral software interfaced with an animal tracking system allows monitoring of the animal''s behavior with precise control of image presentation and reward contingencies for better trained animals. Integration with an in vivo electrophysiological recording system enables examination of behavioral correlates of neural activity at selected epochs of a given cognitive task.We describe protocols for a model system that combines automated visual presentation of information to rodents and intracranial reward with electrophysiological approaches. Our model system offers a sophisticated set of tools as a framework for other cognitive tasks to better isolate and identify specific mechanisms contributing to particular cognitive processes.     

Cognitive disruptions in stress-related psychiatric disorders: A role for corticotropin releasing factor (CRF)

This article is part of a Special Issue “SBN 2014”.Stress is a potential etiology contributor to both post-traumatic stress disorders (PTSD) and major depression. One stress-related neuropeptide that is hypersecreted in these disorders is corticotropin releasing factor (CRF). Dysregulation of CRF has long been linked to the emotion and mood symptoms that characterize PTSD and depression. However, the idea that CRF also mediates the cognitive disruptions observed in patients with these disorders has received less attention. Here we review literature indicating that CRF can alter cognitive functions. Detailed are anatomical studies revealing that CRF is poised to modulate regions required for learning and memory. We also describe preclinical behavioral studies that demonstrate CRF’s ability to alter fear conditioning, impair memory consolidation, and alter a number of executive functions, including attention and cognitive flexibility. The implications of these findings for the etiology and treatment of the cognitive impairments observed in stress-related psychiatric disorders are described.     

Evaluating cognition and thermal physiology as components of the pace-of-life syndrome

The pace-of-life syndrome (POLS) suggests that behavioral traits are correlated and integrate within a fast–slow physiological continuum. At the fast extreme, individuals having higher metabolic rates are more active, exploratory, and bold with the opposite suite of traits characterizing those at the slow physiological extreme. A recent framework suggests that behavioral types may also differ consistently in their cognitive style. Accordingly, we propose that cognition could be further incorporated into the POLS framework comprised of behavioral and thermal physiological traits. Under this premise, fast behavioral types having high thermal traits are predicted to acquire a novel task faster but at the cost of accuracy while slow behavioral types with low thermal traits would be more attentive, responding to cues at a slower rate leading to higher accuracy and flexibility. This was tested by measuring physiological and behavioral traits in delicate skinks (Lampropholis delicata) and testing their learning ability. Correlations were detected between cognition and behavior but not thermal physiology. Contrary to our predictions, individual positioning along these axes opposed our predicted directions along the fast–slow continuum. Fast lizards preferring lower body temperatures expressed higher activity, exploration, sociality, and boldness levels, and learned the discrimination learning task at a slower rate but made the most errors. Additionally, modelling results indicated that neither thermal physiology, behavior, or their interaction influenced cognitive performance. Although the small number of animals completing the final stages of the learning assays limits the strength of these findings. Thus, we propose that future research involving a greater sample size and number of trials be conducted so as to enhance our understanding into how the integration of cognitive style, behavior, and physiology may influence individual fitness within natural populations.     

Cognitive flexibility deficits in a mouse model for the absence of full‐length dystrophin

Duchenne muscular dystrophy (DMD) is a progressive muscle‐wasting disorder, caused by mutations in the DMD gene and the resulting lack of dystrophin. The DMD gene has seven promoters, giving rise to multiple full‐length and shorter isoforms. Besides the expression of dystrophin in muscles, the majority of dystrophin isoforms is expressed in brain and dystrophinopathy can lead to cognitive deficits, including intellectual impairments and deficits in executive function. In contrast to the muscle pathology, the impact of the lack of dystrophin on the brain is not very well studied. Here, we study the behavioral consequences of a lack of full‐length dystrophin isoforms in mdx mice, particularly with regard to domains of executive functions and anxiety. We observed a deficit in cognitive flexibility in mdx mice in the absence of motor dysfunction or general learning impairments using two independent behavioral tests. In addition, increased anxiety was observed, but its expression depended on the context. Overall, these results suggest that the absence of full‐length dystrophin in mice has specific behavioral effects that compare well to deficits observed in DMD patients.     

多巴胺信号系统在衰老引起的行为和认知能力退化中的作用

衰老是生物体随时间推移各项生理功能逐渐发生改变的自然现象。动物的衰老伴随着行为和认知能力的降低,因此研究动物行为和认知功能退化的分子神经机制对于提高老年群体的生活质量具有重要意义。近年来,随着正电子发射断层扫描技术和功能性核磁共振脑成像技术在神经生物学上的广泛运用,越来越多证据表明多巴胺系统功能在衰老过程中显著降低,并且这是人类和动物行为和认知功能退化的重要原因。本文将概述自然衰老过程中多巴胺信号系统功能变化及机制和其在动物行为和认知退化中的作用等方面研究进展。     

The initial stage of reversal learning is impaired in mice hemizygous for the vesicular glutamate transporter (VGluT1)

Behavioral flexibility is a complex cognitive function that is necessary for survival in changeable environments. Patients with schizophrenia or Parkinson's disease often suffer from cognitive rigidity, reducing their capacity to function in society. Patients and rodent models with focal lesions in the prefrontal cortex (PFC) show similar rigidity, owing to the loss of PFC regulation of subcortical reward circuits involved in behavioral flexibility. The vesicular glutamate transporter (VGluT1) is preferentially expressed at modulatory synapses, including PFC neurons that project to components of the reward circuit (such as the nucleus accumbens, NAc). VGluT1^+/? mice display behavioral phenotypes matching many symptoms of schizophrenia, and VGluT1 expression is reduced in the PFC of patients with schizophrenia and Parkinson's disease. Thus, it appears likely that VGluT1‐expressing synapses from PFC play a key role in behavioral flexibility. To examine this hypothesis, we studied behavioral flexibility in VGluT1^+/? mice by testing reversal learning in a visual discrimination task. Here, we show that VGluT1^+/? mice acquired the initial visual discrimination at the same rate as controls. However, they failed to suppress responses to the previously rewarded stimulus following reversal of reward contingencies. Thus, our genetic disruption of modulatory glutamatergic signaling, including that arising from PFC, appears to have impaired the first stage of reversal learning (extinguishing responses to previously rewarded stimuli). Our data show that this deficit stems from a preservative phenotype. These findings suggest that glutamatergic regulation from the cortex is important for behavioral flexibility and the disruption of this pathway may be relevant in diseases such as schizophrenia.     

Neuroanatomical basis of behavioral disturbances in patients with prefrontal lesions

The role of the frontal lobe in control of behavioral and cognitive abilities is explored in a group of 34 patients with brain lesions restricted to the prefrontal cortex. The scores in both structured behavioral questionnaires and standard neuropsychological tests were analyzed using the injured area of the frontal lobe as the independent variable. Our results show that patients with simultaneous lesions in supero- and inferomedial areas of the prefrontal cortex exhibit higher behavioral disturbances. Bilateral lesions also are associated with greater behavioral troubles. On the contrary, cognitive abilities are globally impaired in prefrontal patients. Results are discussed in relation to current models of the organization of the prefrontal cortex and its role on behavior control.     

Behavior and neurobehavioral teratology using the ferret

A behavioral profile of the ferret is presented for those who would like to use this animal in behavioral teratology and toxicology, or other disciplines involving behavior. We have reviewed neurobehavioral teratology of lisencephalic ferrets and neuropsychology of ferrets sustaining frontal lesions, as well as most of the studies of "normal" ferret behavior that have appeared in the research literature. Emphasis is placed on discussion of the tests used and how ferrets behaved on them. The behaviors discussed include spatial (maze) learning, delayed response, visual discrimination learning, discrimination learning sets, schedule maintained behavior, shock avoidance learning and spontaneously occurring behaviors, such as ambulation in open field, spontaneous alternation and species specific behaviors. Although the use of the ferret in behavioral experiments is not yet extensive and large gaps exist in our knowledge about the basic functional capacities of this animal, the ferret is unquestionably well suited for behavioral studies.