Mid-Term and Long-Lasting Psycho-Cognitive Benefits of Bidomain Training Intervention in Elderly Individuals with Mild Cognitive Impairment.

Background: This study investigated whether combining simultaneous physical and cognitive training yields superior cognitive outcomes compared with aerobic training alone in individuals with mild cognitive impairment (MCI) and whether these benefits persist after four weeks of detraining. Methods: Forty-four people with MCI (11 males and 33 females) aged 65 to 75 years were randomly assigned to an 8-week, twice-weekly program of either aerobic training (AT group, n = 15), aerobic training combined with cognitive games (ACT group, n = 15), or simply reading for controls (CG group, n = 14). Selective attention (Stroop), problem-solving (Hanoi Tower), and working memory (Digit Span) tasks were used to assess cognitive performances at baseline, in the 4th (W4) and 8th weeks (W8) of training, and after 4 weeks of rest (W12). Results: Both training interventions induced beneficial effects on all tested cognitive performance at W4 (except for the number of moves in the Hanoi tower task) and W8 (all p <0.001), with the ACT group exhibiting a more pronounced positive impact than the AT group (p < 0.05). This advantage was specifically observed at W8 in tasks such as the Stroop and Tower of Hanoi (% gain ≈40% vs. ≈30% for ACT and AT, respectively) and the digit span test (% gain ≈13% vs. ≈10% for ACT and AT, respectively). These cognitive improvements in both groups, with the greater ones in ACT, persisted even after four weeks of detraining, as evidenced by the absence of a significant difference between W8 and W12 (p > 0.05). Concerning neuropsychological assessments, comparable beneficial effects were recorded following both training regimens (all p < 0.05 from pre- to post-intervention). The control group did not show any significant improvement in most of the cognitive tasks. Conclusions: The greater mid-term and long-lasting effects of combined simultaneous physical-cognitive training underscores its potential as a cost-effective intervention for the prevention and management of cognitive decline. While these results are valuable in guiding optimal physical and mental activity recommendations for adults with MCI, further neurophysiological-based studies are essential to offer robust support and deepen our understanding of the mechanisms underlying these promising findings.

Disruption of amygdala Tsc2 in adolescence leads to changed prelimbic cellular activity and generalized fear responses at adulthood in rats.

Adolescence constitutes a period of vulnerability in the emergence of fear-related disorders (FRD), as a massive reorganization occurs in the amygdala-prefrontal cortex network, critical to regulate fear behavior. Genetic and environmental factors during development may predispose to the emergence of FRD at the adult age, but the underlying mechanisms are poorly understood. In the present study, we tested whether a partial knock-down of tuberous sclerosis complex 2 (Tsc2, Tuberin), a risk gene for neurodevelopmental disorders, in the basolateral amygdala (BLA) from adolescence could alter fear-network functionality and create a vulnerability ground to FRD appearance at adulthood. Using bilateral injection of a lentiviral vector expressing a miRNA against Tsc2 in the BLA of early (PN25) or late adolescent (PN50) rats, we show that alteration induced specifically from PN25 resulted in an increased c-Fos activity at adulthood in specific layers of the prelimbic cortex, a resistance to fear extinction and an overgeneralization of fear to a safe, novel stimulus. A developmental dysfunction of the amygdala could thus play a role in the vulnerability to FRD emergence at adulthood. We propose our methodology as an alternative to model the developmental vulnerability to FRD, especially in its comorbidity with TSC2-related autism syndrome.

Age-related alteration of emotional regulation in the BACHD rat model of Huntington disease.

Huntington's disease (HD) is a genetic neurodegenerative disorder, caused by an expanded CAG repeat in the gene encoding the huntingtin protein. At the premanifest phase, before motor symptoms occur, psychiatric and emotional disorders are observed with high prevalence in HD patients. Agitation, anxiety and irritability are often described but also depression and/or apathy, associated with a lack of emotional control. The aim of the present study was to better circumscribe and understand the emotional symptoms and assess their evolution according to the progression of the disease using a transgenic HD model, BACHD rats, at the age of 4, 12 and 18 months. To achieve this goal, we confronted animals to two types of tests: first, tests assessing anxiety like the light/dark box and the conflict test, which are situations that did not involve an obvious threat and tests assessing the reactivity to a present threat using confrontation with an unknown conspecific (social behavior test) or with an aversive stimulus (fear conditioning test). In all animals, results show an age-dependent anxiety-like behavior, particularly marked in situation requiring passive responses (light/dark box and fear conditioning tests). BACHD rats exhibited a more profound alteration than WT animals in these tests from an early stage of the disease whereas, in tasks requiring some kind of motivation (for food or for social contacts), only old BACHD rats showed high anxiety-like behavior compared to WT, may be partly due to the other symptoms' occurrence at this stage: locomotor difficulties and/or apathy.

Duration-specific effects of outcome devaluation in temporal control are differentially sensitive to amount of training.

This study demonstrates that overtraining in temporal discrimination modifies temporal stimulus control in a bisection task and produces habitual responding, as evidenced through insensitivity to food devaluation. Rats were trained or overtrained in a 2- versus 8-sec temporal discrimination task, with each duration associated with a lever (left or right) and food (grain or sucrose). Overtraining produced a leftward shift in the bisection point. Devaluation treatment induced a differential loss of responding depending on stimulus duration (short versus long) and the level of training (training versus overtraining). The relationships between timing behavior and habitual behavior are discussed.

The Alteration of Emotion Regulation Precedes the Deficits in Interval Timing in the BACHD Rat Model for Huntington Disease.

Huntington disease (HD) is an autosomal dominantly inherited, progressive neurodegenerative disorder which is accompanied by executive dysfunctions and emotional alteration. The aim of the present study was to assess the impact of emotion/stress on on-going highly demanding cognitive tasks, i.e., temporal processing, as a function of age in BACHD rats (a "full length" model of HD). Middle-aged (4-6 months) and old (10-12 months) rats were first trained on a 2 vs. 8-s temporal discrimination task, and then exposed to a series of bisection tests under normal and stressful (10 mild unpredictable foot-shocks) conditions. The animals were then trained on a peak interval task, in which reinforced fixed-interval (FI) 30-s trials were randomly intermixed with non-reinforced probe trials. After training, the effect of stress upon time perception was again assessed. Sensitivity to foot-shocks was also assessed independently. The results show effects of both age and genotype, with largely greater effects in old BACHD animals. The older BACHD animals had impaired learning in both tasks, but reached equivalent levels of performance as WT animals at the end of training in the temporal discrimination task, while remaining impaired in the peak interval task. Whereas sensitivity to foot-shock did not differ between BACHD and WT rats, delivery of foot-shocks during the test sessions had a disruptive impact on temporal behavior in WT animals, an effect which increased with age. In contrast, BACHD rats, independent of age, did not show any significant disruption under stress. In conclusion, BACHD rats showed a disruption in temporal learning in late symptomatic animals. Age-related modification in stress-induced impairment of temporal control of behavior was also observed, an effect which was greatly reduced in BACHD animals, thus confirming previous results suggesting reduced emotional reactivity in HD animals. The results suggest a staggered onset in cognitive and emotional alterations in HD, with emotional alteration being the earliest, possibly related to different time courses of degeneration in cortico-striatal and amygdala circuits.

Altered reactivity of central amygdala to GABAAR antagonist in the BACHD rat model of Huntington disease.

In Huntington's disease (HD), dysfunctional affective processes emerge as key symptoms of disturbances. In human HD and transgenic rat models of the disease, the amygdala was previously shown to have a reduced volume and to carry a high load of mutant huntingtin (mHTT) aggregates. In search of the pathophysiology of affective dysregulation in HD, we hypothesized a specific role of the central amygdala (CeA), known to be particularly involved in emotional regulation. Using transgenic BACHD rats carrying full-length human mHTT, we compared behavioral consequences of pharmacological modulation of CeA function by infusing GABAA receptor (GABAAR) antagonist picrotoxin into ∼4.5 month old BACHD and WT rats before confronting them to potentially threatening situations. Our results show that disinhibition of the CeA induced differential behaviors in WT and BACHD rats in our tasks: it increased social contacts and responses to the threatening warning signal in an avoidance task in BACHD rats but not in WT animals. At the cellular level, analyzes of amygdala alteration/dysfunction showed (1) an age-dependent increase in number and size of mHTT aggregates specifically in the CeA of BACHD rats; (2) no alteration of GABA and GABAAR expression level, but (3) an increased neuronal reactivity (Arc labelling) to a threatening stimulus in the medial part of this nucleus in 4.5 months old BACHD rats. These results suggest a basal pathological hyper-reactivity in the CeA (in particular its medial part) in the transgenic animals. Such amygdala dysfunction could account, at least in part, for affective symptoms in HD patients.

Updating temporal expectancy of an aversive event engages striatal plasticity under amygdala control.

Pavlovian aversive conditioning requires learning of the association between a conditioned stimulus (CS) and an unconditioned, aversive stimulus (US) but also involves encoding the time interval between the two stimuli. The neurobiological bases of this time interval learning are unknown. Here, we show that in rats, the dorsal striatum and basal amygdala belong to a common functional network underlying temporal expectancy and learning of a CS-US interval. Importantly, changes in coherence between striatum and amygdala local field potentials (LFPs) were found to couple these structures during interval estimation within the lower range of the theta rhythm (3-6 Hz). Strikingly, we also show that a change to the CS-US time interval results in long-term changes in cortico-striatal synaptic efficacy under the control of the amygdala. Collectively, this study reveals physiological correlates of plasticity mechanisms of interval timing that take place in the striatum and are regulated by the amygdala.

Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease.

Cognitive deficits associated with Huntington disease (HD) are generally dominated by executive function disorders often associated with disinhibition and impulsivity/compulsivity. Few studies have directly examined symptoms and consequences of behavioral disinhibition in HD and its relation with decision-making. To assess the different forms of impulsivity in a transgenic model of HD (tgHD rats), two tasks assessing cognitive/choice impulsivity were used: risky decision-making with a rat gambling task (RGT) and intertemporal choices with a delay discounting task (DD). To assess waiting or action impulsivity the differential reinforcement of low rate of responding task (DRL) was used. In parallel, the volume as well as cellular activity of the amygdala was analyzed. In contrast to WT rats, 15 months old tgHD rats exhibited a poor efficiency in the RGT task with difficulties to choose advantageous options, a steep DD curve as delays increased in the DD task and a high rate of premature and bursts responses in the DRL task. tgHD rats also demonstrated a concomitant and correlated presence of both action and cognitive/choice impulsivity in contrast to wild type (WT) animals. Moreover, a reduced volume associated with an increased basal cellular activity of the central nucleus of amygdala indicated a dysfunctional amygdala in tgHD rats, which could underlie inhibitory dyscontrol. In conclusion, tgHD rats are a good model for impulsivity disorder that could be used more widely to identify potential pharmacotherapies to treat these invasive symptoms in HD.

The amygdalo-nigrostriatal network is critical for an optimal temporal performance.

The amygdalo-nigrostriatal (ANS) network plays an essential role in enhanced attention to significant events. Interval timing requires attention to temporal cues. We assessed rats having a disconnected ANS network, due to contralateral lesions of the medial central nucleus of the amygdala (CEm) and dopaminergic afferents to the lateral striatum, as compared to controls (sham and ipsilateral lesions of CEm and dopaminergic afferents to LS) in a temporal bisection task. ANS disconnection induced poorer temporal precision and increased response latencies to a short duration. The present results reveal a role of the ANS network in temporal processing.

Impulsivity trait in the early symptomatic BACHD transgenic rat model of Huntington disease.

Impulsivity trait was characterized in 3-5 months old BACHD rats, a transgenic model of Huntington disease, using (1) the delay discounting task to assess cognitive/choice impulsivity, and (2) the Differential Reinforcement of Low Rate of Responding task to evaluate motor/action impulsivity. Transgenic animals showed a high level of choice impulsivity and, to a lesser extent, action impulsivity. Our results provide the first evidence that the transgenic BACHD rat (TG5 line) displays impulsivity disorder as early as 3 months old, as described in early symptomatic HD patients, thus adding to the face validity of the rat model.

Theory of mind and empathy in preclinical and clinical Huntington's disease.

We investigated cognitive and affective Theory of Mind (ToM) and empathy in patients with premanifest and manifest Huntington's disease (HD). The relationship between ToM performance and executive skills was also examined. Sixteen preclinical and 23 clinical HD patients, and 39 healthy subjects divided into 2 control groups were given a French adaptation of the Yoni test (Shamay-Tsoory, S.G., Aharon-Peretz, J. (2007). Dissociable prefrontal networks for cognitive and affective theory of mind: a lesion study. Neuropsychologia, 45(3), 3054-67) that examines first- and second-order cognitive and affective ToM processing in separate conditions with a physical control condition. Participants were also given questionnaires of empathy and cognitive tests which mainly assessed executive functions (inhibition and mental flexibility). Clinical HD patients made significantly more errors than their controls in the first- and second-order cognitive and affective ToM conditions of the Yoni task, but exhibited no empathy deficits. However, there was no evidence that ToM impairment was related to cognitive deficits in these patients. Preclinical HD patients were unimpaired in ToM tasks and empathy measures compared with their controls. Our results are consistent with the idea that impaired affective and cognitive mentalizing emerges with the clinical manifestation of HD, but is not necessarily part of the preclinical stage. Furthermore, these impairments appear independent of executive dysfunction and empathy.

Reduced impact of emotion on choice behavior in presymptomatic BACHD rats, a transgenic rodent model for Huntington Disease.

Executive dysfunction and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder genetically characterized by expanded CAG repeats in the HTT gene. Using the BACHD rat model of HD (97 CAG-CAA repeats), the present research seeks to characterize the progressive emergence of decision-making impairments in a rat version of the Iowa Gambling Task (RGT) and the impact of emotional modulation, whether positive or negative, on choice behavior. The choice efficiency shown both by WT rats (independent of their age) and the youngest BACHD rats (2 and 8months old) evidenced that they are able to integrate outcomes of past decisions to determine expected reward values for each option. However, 18months old BACHD rats made fewer choices during the RGT session and were less efficient in choosing advantageous options than younger animals. Presenting either chocolate pellets or electrical footshocks half-way through a second RGT session reduced exploratory activity (inefficient nose-poking) and choices with a weaker effect on BACHD animals than on WT. Choice efficiency was left intact in transgenic rats. Our results bring new knowledge on executive impairments and impact of emotional state on decision-making at different stages of the disease, increasing the face-validity of the BACHD rat model.

Cognitive dysfunction in the dystrophin-deficient mouse model of Duchenne muscular dystrophy: A reappraisal from sensory to executive processes.

Duchenne muscular dystrophy (DMD) is associated with language disabilities and deficits in learning and memory, leading to intellectual disability in a patient subpopulation. Recent studies suggest the presence of broader deficits affecting information processing, short-term memory and executive functions. While the absence of the full-length dystrophin (Dp427) is a common feature in all patients, variable mutation profiles may additionally alter distinct dystrophin-gene products encoded by separate promoters. However, the nature of the cognitive dysfunctions specifically associated with the loss of distinct brain dystrophins is unclear. Here we show that the loss of the full-length brain dystrophin in mdx mice does not modify the perception and sensorimotor gating of auditory inputs, as assessed using auditory brainstem recordings and prepulse inhibition of startle reflex. In contrast, both acquisition and long-term retention of cued and trace fear memories were impaired in mdx mice, suggesting alteration in a functional circuit including the amygdala. Spatial learning in the water maze revealed reduced path efficiency, suggesting qualitative alteration in mdx mice learning strategy. However, spatial working memory performance and cognitive flexibility challenged in various behavioral paradigms in water and radial-arm mazes were unimpaired. The full-length brain dystrophin therefore appears to play a role during acquisition of associative learning as well as in general processes involved in memory consolidation, but no overt involvement in working memory and/or executive functions could be demonstrated in spatial learning tasks.

Disrupted sensorimotor synchronization, but intact rhythm discrimination, in children treated for a cerebellar medulloblastoma.

The aim of this study was to investigate the temporal abilities of children treated by surgery for a malignant tumor in the cerebellum, both in the perception and the production of rhythm. Children with a diagnosed medulloblastoma and age-matched control children were tested in a rhythm discrimination task and a sensorimotor synchronization task. Their motor and cognitive capabilities were also assessed through a battery of age-adapted neuropsychological tests. The results did not show any significant difference in performance between groups for the discrimination task. On the contrary, children with cerebellar lesions produced longer and more variable inter-tap intervals (ITI) in their spontaneous motor tempo (SMT) than did the control children. However, the length and, to a lesser extent, the variability of their SMT decreased after a synchronization phase, when they had been instructed to tap in synchrony with a beep. During the synchronization task, the children with medulloblastoma succeeded to modify the length of their ITI in response to an auditory rhythm, although with better success when the inter-stimuli intervals (ISI) were shorter than when they were longer than the ITIs of their own SMT. Correlational analyses revealed that children's poorer synchronization performance was related to lower scores in neuropsychological tests assessing motor dexterity and processing speed.

Modified impact of emotion on temporal discrimination in a transgenic rat model of Huntington disease.

Huntington's disease (HD) is characterized by triad of motor, cognitive, and emotional symptoms along with neuropathology in fronto-striatal circuit and limbic system including amygdala. Emotional alterations, which have a negative impact on patient well-being, represent some of the earliest symptoms of HD and might be related to the onset of the neurodegenerative process. In the transgenic rat model (tgHD rats), evidence suggest emotional alterations at the symptomatic stage along with neuropathology of the central nucleus of amygdala (CE). Studies in humans and animals demonstrate that emotion can modulate time perception. The impact of emotion on time perception has never been tested in HD, nor is it known if that impact could be part of the presymptomatic emotional phenotype of the pathology. The aim of this paper was to characterize the effect of emotion on temporal discrimination in presymptomatic tgHD animals. In the first experiment, we characterized the acute effect of an emotion (fear) conditioned stimulus on temporal discrimination using a bisection procedure, and tested its dependency upon an intact central amygdala. The second experiment was aimed at comparing presymptomatic homozygous transgenic animals at 7-months of age and their wild-type littermates (WT) in their performance on the modulation of temporal discrimination by emotion. Our principal findings show that (1) a fear cue produces a short-lived decrease of temporal precision after its termination, and (2) animals with medial CE lesion and presymptomatic tgHD animals demonstrate an alteration of this emotion-evoked temporal distortion. The results contribute to our knowledge about the presymptomatic phenotype of this HD rat model, showing susceptibility to emotion that may be related to dysfunction of the central nucleus of amygdala.

Cerebellar deep nuclei involvement in cognitive adaptation and automaticity.

To determine the role of the interpositus nuclei of cerebellum in rule-based learning and optimization processes, we studied (1) successive transfers of an initially acquired response rule in a cross maze and (2) behavioral strategies in learning a simple response rule in a T maze in interpositus lesioned rats (neurotoxic or electrolytic lesions). Even though lesioned animals showed no impairment in learning the initial stimulus-response association, they had difficulties in transferring the acquired adapted response rule, and in optimizing their response strategy. These results add information on the role of interpositus nuclei in adaptation to environmental changes.

Time perception in children treated for a cerebellar medulloblastoma.

The aim of the present study was to investigate temporal abilities in children treated by surgery for a malignant tumor in the cerebellum. Children with a diagnosed medulloblastoma and age-paired control children were given a temporal discrimination task (bisection task) and a temporal reproduction task with two duration ranges, one shorter than 1s and the other longer than 4s. The motor and cognitive capacities of these children were also assessed by a battery of age-adapted neuropsychological tests. The results did not show any significant difference in performance between the children with or without cerebellar lesions in the temporal discrimination task. It was only in the temporal reproduction task that the children with cerebellar lesions reproduced longer and more variable durations than the other children, but only for the short stimulus durations (≤ 1 s). In addition, a hierarchical regression analysis revealed that the best predictor of variance in temporal performance was a significantly lower processing speed in children with cerebellar lesions in comparison to their controls. These results indicated that the major cause of deficits in temporal judgments in children with cerebellar lesions was due to their inability to reproduce accurately short temporal intervals in association with low processing speed, rather than to a specific deficit in the perception of time.

Temporal sensitivity changes with extended training in a bisection task in a transgenic rat model.

The present study investigated temporal perception in a Huntington disease transgenic rat model using a temporal bisection procedure. After initial discrimination training in which animals learned to press one lever after a 2-s tone duration, and the other lever after a 8-s tone duration for food reward, the bisection procedure was implemented in which intermediate durations with no available reinforcement were interspersed with trials with the anchor durations. Bisection tests were repeated in a longitudinal design from 4 to 8 months of age. The results showed that response latencies evolved from a monotonic step-function to an inverted U-shaped function with repeated testing, a precursor of non-responding on trials with intermediate durations. We inferred that temporal sensitivity and incentive motivation combined to control the transformation of the bisection task from a two-choice task at the outset of testing to a three-choice task with repeated testing. Changes in the structure of the task and/or continued training were accompanied by improvement in temporal sensitivity. In sum, the present data highlight the possible joint roles of temporal and non-temporal factors in the temporal bisection task, and suggested that non-temporal factors may compensate for deficits in temporal processing.

Behavioral and in vivo electrophysiological evidence for presymptomatic alteration of prefrontostriatal processing in the transgenic rat model for huntington disease.

Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4- to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta-burst stimulation (TBS) were assessed. Results showed an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after TBS in homozygous transgenic rats. Results from the heterozygous animals mostly fell between wild-type and homozygous transgenic rats. Our results suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the present study provides the first behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD.

Cognitive processing impairments in a supra-second temporal discrimination task in rats with cerebellar lesion.

The role of interpositus nuclei (IN) in timing in the sub-second range is well supported in eyeblink conditioning studies. Timing impairments shown in the seconds range in patients with intermediate cerebellar lesion, and known intermediate cerebellar cortex projection to IN raise the question of a possible involvement of IN in timing in the supra-second range as well. To address this question, we tested rats (Sprague-Dawley) given bilateral lesions of IN with Colchicine in a 2- vs. 8-s temporal discrimination task, followed by three daily sessions of a temporal bisection tests with five added intermediate non-reinforced durations. IN lesioned rats showed normal acquisition of the temporal discrimination, but a transient impairment of temporal sensitivity during the bisection tests. In addition, their response latencies suggested a different behavioral strategy from that of control animals. Our results indicate that the IN of the cerebellum may not be critically involved in temporal processing in the 2-8 s range, but may play a role in the cognitive processes that access temporal information in the mediation of choice behavior.