Conditioning and pseudoconditioning differently change intrinsic excitability of inhibitory interneurons in the neocortex.

Many studies indicate a broad role of various classes of GABAergic interneurons in the processes related to learning. However, little is known about how the learning process affects intrinsic excitability of specific classes of interneurons in the neocortex. To determine this, we employed a simple model of conditional learning in mice where vibrissae stimulation was used as a conditioned stimulus and a tail shock as an unconditioned one. In vitro whole-cell patch-clamp recordings showed an increase in intrinsic excitability of low-threshold spiking somatostatin-expressing interneurons (SST-INs) in layer 4 (L4) of the somatosensory (barrel) cortex after the conditioning paradigm. In contrast, pseudoconditioning reduced intrinsic excitability of SST-LTS, parvalbumin-expressing interneurons (PV-INs), and vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) with accommodating pattern in L4 of the barrel cortex. In general, increased intrinsic excitability was accompanied by narrowing of action potentials (APs), whereas decreased intrinsic excitability coincided with AP broadening. Altogether, these results show that both conditioning and pseudoconditioning lead to plastic changes in intrinsic excitability of GABAergic interneurons in a cell-specific manner. In this way, changes in intrinsic excitability can be perceived as a common mechanism of learning-induced plasticity in the GABAergic system.

Hydrocortisone Differentially Affects Reinstatement of Pain-related Responses in Patients With Chronic Back Pain and Healthy Volunteers.

Despite the crucial role of effective and sustained extinction of conditioned pain-related fear in cognitive-behavioral treatment approaches for chronic pain, experimental research on extinction memory retrieval in chronic pain remains scarce. In healthy populations, extinction efficacy of fear memory is affected by stress. Therefore, we investigated the effects of oral hydrocortisone administration on the reinstatement of pain-related associations in 57 patients with non-specific chronic back pain (CBP) and 59 healthy control (HC) participants in a differential pain-related conditioning paradigm within a placebo-controlled, randomized, and double-blind design. Participants' skin conductance responses indicate hydrocortisone-induced reinstatement effects in HCs but no observable reinstatement in HCs receiving placebo treatment. Interestingly, these effects were reversed in patients with CBP, that is, reinstatement responses were only observed in the placebo and not in the hydrocortisone group. Our findings corroborate previous evidence of stress-induced effects on extinction efficacy and reinstatement of fear memory in HCs, extending them into the pain context, and call for more research to clarify the role of stress in fear extinction and return of fear phenomena possibly contributing to treatment failure in chronic pain treatment. PERSPECTIVE: Opposing effects in HCs and patients with non-specific CBP may be associated with changes in the patients' stress systems. These findings could be of relevance to optimizing psychological, extinction-based treatment approaches.

Genetic and environmental influences on one-trial conditioned context aversion in mice.

Anticipatory nausea (AN) is caused by an association between contextual cues and the experience of nausea (the side effects of chemotherapy or radiation treatment) and it develops predominantly in female patients undergoing chemotherapy. Preclinical studies in rodents show that the administration of an illness-inducing agent in the presence of novel contextual cues can cause conditioned context aversion (CCA) and this has been proposed to model AN. The literature also suggests that brief pre-exposure to a novel context prior to shock delivery is critical in the development of contextual fear conditioning in rodents (a phenomenon known as Immediate Shock Deficit), but this has not been assessed in CCA. The aim of present study was to develop a CCA paradigm to assess this in outbred (CD1) and inbred (C57BL/6J) mice and evaluate potential sex differences. The results revealed that a single conditioning trial in which a distinctive context was paired with LiCl-induced illness was sufficient to elicit a conditioned response in both female and male CD1 outbred mice, but not in C57BL/6J inbred mice. In addition, CCA was facilitated when animals had prior experience with the context. Finally, outbred female mice showed longer and more robust retention of CCA than male mice, which parallels clinical findings. The results indicate the importance of using CD1 outbred mice as an animal model of AN as well as examining sex differences in the CCA paradigm. Similar findings in humans encourage the future use of this novel CCA preclinical mouse model.

Attenuating experimentally acquired disgust: Comparing counterconditioning, exposure and unconditioned stimulus revaluation.

BACKGROUND AND OBJECTIVES: Disgust is implicated in the aetiology and maintenance of various psychopathologies such as anxiety disorders and obsessive-compulsive disorders. Despite its prominent role in psychopathology, little is known about how to effectively attenuate disgust. The study examined strategies to modify an experimentally acquired disgust response in a sample of undergraduate students. METHODS: A conditioning paradigm was used where participants (N = 175) first underwent acquisition of disgust via repeated presentations of a neutral picture (functioning as conditioned stimulus + [CS+]) paired with a disgusting picture (functioning as unconditioned stimulus [US]). Participants were then randomly assigned to either an exposure (repeated presentation of CS-only trials), counterconditioning (pairing CS+ with pleasant pictures), US revaluation (pairing disgusting US with pleasant pictures) or a control (filler task) condition. We hypothesised that counterconditioning would attenuate evaluative learned disgust to the greatest extent, relative to exposure and US revaluation. Participants' evaluations of the pictures were attained with a disgust-pleasantness visual analogue scale. RESULTS: Exposure, counterconditioning and US revaluation reduced disgusting US expectancies. However, experimental and control conditions did not differ in terms of attenuating disgust towards CS+. LIMITATIONS: Measures of psychopathology and implicit evaluations of disgust were not collected. Modest power might have limited significance of the results. CONCLUSIONS: No statistical support for the effectiveness of disgust attenuation following exposure nor counterconditioning were found. Findings for US revaluation are inconclusive. Implications for future research are discussed.

Cerebellum-dependent associative learning is not impaired in a mouse model of neurofibromatosis type 1.

Individuals with Neurofibromatosis type 1 (NF1) experience a high degree of motor problems. The cerebellum plays a pivotal role in motor functioning and the NF1 gene is highly expressed in cerebellar Purkinje cells. However, it is not well understood to what extent NF1 affects cerebellar functioning and how this relates to NF1 motor functioning. Therefore, we subjected global Nf1+/- mice to a cerebellum-dependent associative learning task, called Pavlovian eyeblink conditioning. Additionally, we assessed general motor function and muscle strength in Nf1+/- mice. To our surprise, we found that Nf1+/- mice showed a moderately increased learning rate of conditioned eyeblink responses, as well as improved accuracy in the adaptive timing of the eyeblink responses. Locomotion, balance, general motor function, and muscle strength were not affected in Nf1+/- mice. Together, our results support the view that cerebellar function in Nf1+/- mice is unimpaired.

Impact of hormonal contraceptives on sex differences in fear conditioning and fear extinction in PTSD.

Sex differences in the neurobiological mechanisms involved in fear conditioning and extinction have been suggested to contribute to differential vulnerability for the development of posttraumatic stress disorder (PTSD) in women compared with men. Reproductive hormones, such as estradiol, have been shown to facilitate fear conditioning and extinction learning and may explain some of these differences. However, the effect of commonly used hormonal contraceptives on the neurobiological mechanisms of fear conditioning and extinction is poorly understood. A laboratory study was conducted in trauma-exposed men and women with and without full or partial PTSD to examine effects of sex and use of hormonal birth control on fear conditioning, fear extinction learning, and extinction retention. Participants underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS-) with shock. Extinction learning occurred 72 h later, and extinction retention was tested 1 wk after extinction. Women on hormonal contraceptives (HCs) demonstrated enhanced acquisition of fear conditioning and enhanced extinction of fear as compared with women off hormonal birth control and men. While clinical implications have yet to be determined, these results suggest that hormonal contraceptives may facilitate learning during both fear acquisition and extinction. Understanding the impact of sex and hormones on fear conditioning and extinction processes may lead to new insights into the pathophysiology of PTSD and result in advancements in treatment that may vary by sex.

Facilitated extinction of conditioned fear responses by delta 9-tetrahyrdrocannabidol in humans: a pilot study.

OBJECTIVE: We sought to determine whether acute delta 9-tetrahyrdrocannabidol (THC) administration would facilitate fear extinction in young occasional cannabis users, given that animal models indicate THC facilitates extinction learning, and recent studies indicate THC administration may also enhance threat memory extinction in humans. METHODS: On each of the 2 days, 24+ hour THC-deprived participants were conditioned to fear visual stimuli in a delay conditioning and extinction paradigm. Both CS+ and CS- were faces of negative emotional valence, with the CS+ paired with mild electric shock. Throughout both conditioning and extinction paradigms, EEG was measured to quantify event-related potentials for these learning processes. Following conditioning, individuals, in a randomized and counter-balanced order, smoked either an active THC cigarette (26.25 mg/2.7% THC) or a placebo marijuana cigarette (0.002% THC) on 1 day and the opposite cigarette on the second day. After smoking, CS+ and CS- were presented without shock, resulting in extinction of conditioned fear. RESULTS: Relative to placebo, THC facilitated extinction of the conditioned response to the CS+, as reflected by reductions in late positive potential amplitude during extinction learning. CONCLUSIONS: The results indicate that acute THC administration may facilitate extinction of the conditioned fear response in humans.

Estradiol during (analogue-)trauma: Risk- or protective factor for intrusive re-experiencing?

Intrusions, a key symptom of posttraumatic stress disorder (PTSD), can occur in the form of images but also as pain sensations. Similar to audiovisual intrusions, the frequency and persistence of pain intrusions varies greatly between individuals. In the current study, we examined whether peritraumatic circulating 17ß-estradiol (E2) levels are a biologic factor associated with subsequent audiovisual (i.e., film) and pain intrusion development, and whether peritraumatic stress levels modulate this relationship. Forty-one free-cycling women participated in an ecologically informed trauma-pain-conditioning (TPC) paradigm, using trauma-films and pain as unconditioned stimuli. Independent variables were salivary peritraumatic E2 levels and stress indexed by salivary cortisol and self-reported state-anxiety during TPC. Outcomes were film- and pain-intrusions occurring during daily-life in the week following TPC and a Memory-Triggering-Task in response to conditioned stimuli 24 h after TPC. In the week after analogue-trauma, higher peritraumatic E2 levels were associated with a greater probability of experiencing film-intrusions in the beginning of the week, which switched to a lower probability toward the end of the week. This time-dependent relationship between E2 and film-intrusions only held for higher state-anxious women. In contrast, results indicated a consistent inverse relationship between peritraumatic E2 levels and pain-intrusions during daily-life and Memory-Triggering-Task. Together, these data suggest that higher peritraumatic E2 levels could be associated with lower long-term visual trauma intrusions, as well as lower pain-intrusions, and thereby possibly constitute a protective biologic factor for PTSD and potentially also for chronic pain.

Common and separable behavioral and neural mechanisms underlie the generalization of fear and disgust.

Generalization represents the transfer of a conditioned responses to stimuli that resemble the conditioned stimulus (CS). Previous studies on generalization of defensive avoidance responses have primarily focused on fear and have neglected disgust generalization, which represents a key pathological mechanism in some anxiety disorders. In the present study we examined common and distinct mechanisms of fear and disgust generalization by means of a fear or disgust multi-CS conditioning and generalization paradigm with concomitant event-related potential (ERPs) acquisition in n = 62 subjects. We demonstrate that compared to fear, disgust-relevant generalized stimuli (GS) elicited larger expectancy ratings and longer reaction times (RTs) reflecting stronger ratings of 'risk'. On the electrophysiological level, increased P2 amplitudes were found in response to conditioned CS+ versus CS- across both domains, possibly reflecting higher motivational and attentional salience of aversive conditioned stimuli per se. Contingent negative variation (CNV) amplitude was significantly larger for disgust-CS+ than disgust-CS-, reflecting a stronger preparation of the disgust US. Additionally, we found that the contingent negative variation (CNV) fear generalization gradient, and CNV amplitude were increased with similarity to CS+. In contrast the CNV to disgust-GS did not differ and did not reflect disgust generalization. Together this may indicate that the CNV represents a highly fear-specific index for generalization learning. This study provides the first neurobiological evidence for common and distinct generalization learning in fear versus disgust suggesting that dysregulations in separable defensive avoidance mechanisms may underly different anxiety disorder subtypes.

Helpless against food cues: the influence of pro- and anti-sugar videos on instrumental food-seeking behaviour in a Pavlovian-to-instrumental transfer paradigm.

OBJECTIVE: External food cues can trigger food seeking by means of associative Stimulus-Outcome-Response learning mechanisms. These mechanisms can contribute to cued overeating. The present study aims at investigating if (cued) food-seeking behaviour can be influenced by pro- and anti-sugar videos. DESIGN: Participants (N = 81) completed a Pavlovian-to-instrumental transfer (PIT) task: in an instrumental training, they learned associations between button presses and resulting sugary or sugar-free snacks. In a subsequent Pavlovian training, the snacks were paired with different cues. During the following transfer test, participants performed free button presses to win snacks while the cues were present or not. MAIN OUTCOME MEASURES: The number of button presses for the different snacks in the transfer test was analysed. RESULTS: We observed an outcome specific PIT effect, i.e. higher response rates for cued snacks. The videos did not affect the PIT effect. However, exploratory analyses revealed that the anti-sugar video led to fewer button presses for sugary snacks (compared to the pro-sugar video). CONCLUSION: While snack-seeking behaviour was unaffected by the video's messages in the presence of food cues, in the absence of food cues there was evidence for a reduction of sugary snack choices by the anti-sugar video.

Comparative metabolic profiling of posterior parietal cortex, amygdala, and hippocampus in conditioned fear memory.

Fear conditioning and retrieval are suitable models to investigate the biological basis of various mental disorders. Hippocampus and amygdala neurons consolidate conditioned stimulus (CS)-dependent fear memory. Posterior parietal cortex is considered important for the CS-dependent conditioning and retrieval of fear memory. Metabolomic screening among functionally related brain areas provides molecular signatures and biomarkers to improve the treatment of psychopathologies. Herein, we analyzed and compared changes of metabolites in the hippocampus, amygdala, and posterior parietal cortex under the fear retrieval condition. Metabolite profiles of posterior parietal cortex and amygdala were similarly changed after fear memory retrieval. While the retrieval of fear memory perturbed various metabolic pathways, most metabolic pathways that overlapped among the three brain regions had high ranks in the enrichment analysis of posterior parietal cortex. In posterior parietal cortex, the most perturbed pathways were pantothenate and CoA biosynthesis, purine metabolism, glutathione metabolism, and NAD+ dependent signaling. Metabolites of posterior parietal cortex including 4'-phosphopantetheine, xanthine, glutathione, ADP-ribose, ADP-ribose 2'-phosphate, and cyclic ADP-ribose were significantly regulated in these metabolic pathways. These results point to the importance of metabolites of posterior parietal cortex in conditioned fear memory retrieval and may provide potential biomarker candidates for traumatic memory-related mental disorders.

Role of prediction error and the cholinergic system on memory reconsolidation processes in mice.

The ability to make predictions based on stored information is a general coding strategy. A prediction error (PE) is a mismatch between expected and current events. Our memories, like ourselves, are subject to change. Thus, an acquired memory can become active and update its content or strength by a labilization-reconsolidation process. Within the reconsolidation framework, PE drives the updating of consolidated memories. In the past our lab has made key progresses showing that a blockade in the central cholinergic system during reconsolidation can cause memory impairment, while reinforcement of cholinergic activity enhances it. In the present work we determined that PE is a necessary condition for memory to reconsolidate in an inhibitory avoidance task using both male and female mice. Depending on the intensity of the unconditioned stimulus (US) used during training, a negative (higher US intensity) or positive (lower US intensity/no US) PE on a retrieval session modified the behavioral response on a subsequent testing session. Furthermore, we demonstrated that the cholinergic system modulates memory reconsolidation only when PE is detected. In this scenario administration of oxotremorine, scopolamine or nicotine after memory reactivation either enhanced or impaired memory reconsolidation in a sex-specific manner.

Calcitonin gene related peptide α is dispensable for many danger-related motivational responses.

Calcitonin gene related peptide (CGRP) expressing neurons in the parabrachial nucleus have been shown to encode danger. Through projections to the amygdala and other forebrain structures, they regulate food intake and trigger adaptive behaviors in response to threats like inflammation, intoxication, tumors and pain. Despite the fact that this danger-encoding neuronal population has been defined based on its CGRP expression, it is not clear if CGRP is critical for its function. It is also not clear if CGRP in other neuronal structures is involved in danger-encoding. To examine the role of CGRP in danger-related motivational responses, we used male and female mice lacking αCGRP, which is the main form of CGRP in the brain. These mice had no, or only very weak, CGRP expression. Despite this, they did not behave differently compared to wildtype mice when they were tested for a battery of danger-related responses known to be mediated by CGRP neurons in the parabrachial nucleus. Mice lacking αCGRP and wildtype mice showed similar inflammation-induced anorexia, conditioned taste aversion, aversion to thermal pain and pain-induced escape behavior, although it should be pointed out that the study was not powered to detect any possible differences that were minor or sex-specific. Collectively, our findings suggest that αCGRP is not necessary for many threat-related responses, including some that are known to be mediated by CGRP neurons in the parabrachial nucleus.

Effect of histone acetylation on maintenance and reinstatement of morphine-induced conditioned place preference and ΔFosB expression in the nucleus accumbens and prefrontal cortex of male rats.

Recently, epigenetic mechanisms are considered as the new potential targets for addiction treatment. This research was designed to explore the effect of histone acetylation on ΔFosB gene expression in morphine-induced conditioned place preference (CPP) in male rats. CPP was induced via morphine injection (5 mg/kg) for three consecutive days. Animals received low-dose theophylline (LDT) or Suberoylanilide Hydroxamic acid (SAHA), as an histone deacetylase (HDAC) activator or inhibitor, respectively, and a combination of both in subsequent extinction days. Following extinction, a priming dose of morphine (1 mg/kg) was administered to induce reinstatement. H4 acetylation and ΔFosB expression in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were assessed on the last day of extinction and the following CPP reinstatement. Our results demonstrated that daily administration of SAHA (25 mg/kg; i.p.), facilitated morphine-extinction and decreased CPP score in reinstatement of place preference. Conversely, injections of LDT (20 mg/kg; i.p.) prolonged extinction in animals. Co-administration of LDT and SAHA on extinction days counterbalanced each other, such that maintenance and reinstatement were no different than the control group. The gene expression of ΔFosB was increased by SAHA in NAc and mPFC compared to the control group. Administration of SAHA during extinction days, also altered histone acetylation in the NAc and mPFC on the last day of extinction, but not on reinstatement day. Collectively, administration of SAHA facilitated extinction and reduced reinstatement of morphine-induced CPP in rats. This study confirms the essential role of epigenetic mechanisms, specifically histone acetylation, in regulating drug-induced plasticity and seeking behaviors.

Extended operant training increases infralimbic and prelimbic cortex Fos regardless of fear conditioning experience.

Extended fear training can lead to initially low fear expression that grows over time, termed fear incubation. Conversely, a single fear conditioning session typically results in high fear initially that is sustained over time. Fear expression decreases across extended training, suggesting that a fear extinction-like process might be responsible for low fear observed soon after training. Because of the prominent role medial prefrontal cortex (mPFC) plays in fear conditioning and extinction, we decided to examine Fos expression resulting from a cued fear retrieval test to gain insight into possible mechanisms involved in extended training fear incubation. Male Long-Evans rats received 1 or 10 days of tone-shock pairings or tone-only exposure (while lever-pressing for food). Two days after the end of fear training, rats received a cued fear test, with perfusions timed to visualize Fos expression during test. As expected, the limited fear conditioning group exhibited higher fear in the test than any of the other groups (as measured with conditioned suppression of lever-pressing). Interestingly, we found that extended training animals (whether they received tone-shock pairings or tone-only exposure) expressed higher levels of Fos in both prelimbic and infralimbic cortices than limited training animals. There was no association between fear expression and mPFC Fos expression. These results suggest we may have visualized Fos expression related to operant overtraining rather than conditioned fear related processes. Further research is needed to determine the neurobiological basis of extended training fear incubation and to determine processes represented by the pattern of Fos expression we observed.

Sex differences in fear memory consolidation via Tac2 signaling in mice.

Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. Moreover, more specific treatments for fear-related disorders such as posttraumatic stress disorder and phobias may help to decrease their negative impact on mental health. In this line, the Tachykinin 2 (Tac2) pathway in the central amygdala (CeA) has been shown to be sufficient and necessary for the modulation of fear memory consolidation. CeA-Tac2 antagonism and its pharmacogenetic temporal inhibition impair fear memory in male mice. Surprisingly, we demonstrate here the opposite effect of Tac2 blockade on enhancing fear memory consolidation in females. Furthermore, we show that CeA-testosterone in males, CeA-estradiol in females and Akt/GSK3ß/ß-Catenin signaling both mediate the opposite-sex differential Tac2 pathway regulation of fear memory.

Impaired contextual fear conditioning in RasGRF2 mutant mice is likely Ras-ERK-dependent.

Ras/Raf/MEK/ERK (Ras-ERK) signaling has been shown to play an important role in fear acquisition. However, little information is known regarding the mechanisms that contribute to the regulation of this pathway in terms of the learning of conditioned fears. Ras Guanine Nucleotide Releasing Factor 2 (RasGRF2) is one of two guanine nucleotide exchange factors (GEF) that regulates the Ras-ERK signaling pathway in a Ca2+-dependent manner via control of the cycling of Ras isoforms between an inactive and active state. Here we sought to determine the role of RasGRF2 on contextual fear conditioning in RasGRF2 knockout (KO) and their wild type (WT) counterparts. Male KO and WT mice underwent a single session of contextual fear conditioning (12 min, 4 unsignaled shocks), followed by either daily 12-min retention trials or the molecular analysis of Ras activation and pERK1/2 activity. KO mice showed an impaired acquisition of contextual fear, as demonstrated by reduced freezing during fear conditioning and 24-hr retention tests relative to WT mice. Ras analysis following fear conditioning demonstrated a reduction in Ras activation in the hippocampus as well as a reduction in pERK1/2 in the CA1 region of the hippocampus in KO mice, suggesting that the decrease in fear conditioning in KO mice is at least in part due to the impairment of Ras-ERK signaling in the hippocampus during learning. These data indicate a role for RasGRF2 in contextual fear conditioning in mice that may be Ras-ERK-dependent.

Functional interplay between adenosine A2A receptor and NMDA preconditioning in fear memory and glutamate uptake in the mice hippocampus.

N-methyl D-aspartate (NMDA) administered at subtoxic dose plays a protective role against neuronal excitotoxicity, a mechanism described as preconditioning. Since the activation of adenosinergic receptors influences the achievement of NMDA preconditioning in the hippocampus, we evaluated the potential functional interplay between adenosine A1 and A2A receptors (A1R and A2AR) activities and NMDA preconditioning. Adult male Swiss mice received saline (NaCl 0.9 g%, i.p.) or a nonconvulsant dose of NMDA (75 mg/kg, i.p.) and 24 h later they were treated with the one of the ligands: A1R agonist (CCPA, 0.2 mg/kg, i.p.) or antagonist (DPCPX, 3 mg/kg, i.p.), A2AR agonist (CGS21680, 0.05 mg/kg, i.p.) or antagonist (ZM241385, 0.1 mg/kg, i.p.) and subjected to contextual fear conditioning task. Binding properties and content of A2AR and glutamate uptake were assessed in the hippocampus of mice subjected to NMDA preconditioning. Treatment with CGS21680 increased the time of freezing during the exposure of animals to the new environment. NMDA preconditioning did not affect the freezing time of mice per se, but it prevented the response observed after the activation of A2AR. Furthermore, the activation of A2AR by CGS21680 after the preconditioning blocked the increase of glutamate uptake induced by NMDA preconditioning. The immunodetection of A2AR in total hippocampal homogenates showed no significant differences evoked by NMDA preconditioning and did not alter A2AR maximum binding for the selective ligand [3H]CGS21680. These results demonstrate changes in A2AR functionality in mice following NMDA preconditioning.

Conditional knockout of MET receptor tyrosine kinase in cortical excitatory neurons leads to enhanced learning and memory in young adult mice but early cognitive decline in older adult mice.

Human genetic studies established MET gene as a risk factor for autism spectrum disorders. We have previously shown that signaling mediated by MET receptor tyrosine kinase, expressed in early postnatal developing forebrain circuits, controls glutamatergic neuron morphological development, synapse maturation, and cortical critical period plasticity. Here we investigated how MET signaling affects synaptic plasticity, learning and memory behavior, and whether these effects are age-dependent. We found that in young adult (postnatal 2-3 months) Met conditional knockout (Metfx/fx:emx1cre, cKO) mice, the hippocampus exhibits elevated plasticity, measured by increased magnitude of long-term potentiation (LTP) and depression (LTD) in hippocampal slices. Surprisingly, in older adult cKO mice (10-12 months), LTP and LTD magnitudes were diminished. We further conducted a battery of behavioral tests to assess learning and memory function in cKO mice and littermate controls. Consistent with age-dependent LTP/LTD findings, we observed enhanced spatial memory learning in 2-3 months old young adult mice, assessed by hippocampus-dependent Morris water maze test, but impaired spatial learning in 10-12 months mice. Contextual and cued learning were further assessed using a Pavlovian fear conditioning test, which also revealed enhanced associative fear acquisition and extinction in young adult mice, but impaired fear learning in older adult mice. Lastly, young cKO mice also exhibited enhanced motor learning. Our results suggest that a shift in the window of synaptic plasticity and an age-dependent early cognitive decline may be novel circuit pathophysiology for a well-established autism genetic risk factor.

Resection of cerebellar tumours causes widespread and functionally relevant white matter impairments.

Several diffusion tensor imaging studies reveal that white matter (WM) lesions are common in children suffering from benign cerebellar tumours who are treated with surgery only. The clinical implications of WM alterations that occur as a direct consequence of cerebellar disease have not been thoroughly studied. Here, we analysed structural and diffusion imaging data from cerebellar patients with chronic surgical lesions after resection for benign cerebellar tumours. We aimed to elucidate the impact of focal lesions of the cerebellum on WM integrity across the entire brain, and to investigate whether WM deficits were associated with behavioural impairment in three different motor tasks. Lesion symptom mapping analysis suggested that lesions in critical cerebellar regions were related to deficits in savings during an eyeblink conditioning task, as well as to deficits in motor action timing. Diffusion imaging analysis of cerebellar WM indicated that better behavioural performance was associated with higher fractional anisotropy (FA) in the superior cerebellar peduncle, cerebellum's main outflow path. Moreover, voxel-wise analysis revealed a global pattern of WM deficits in patients within many cerebral WM tracts critical for motor and non-motor function. Finally, we observed a positive correlation between FA and savings within cerebello-thalamo-cortical pathways in patients but not in controls, showing that saving effects partly depend on extracerebellar areas, and may be recruited for compensation. These results confirm that the cerebellum has extended connections with many cerebral areas involved in motor/cognitive functions, and the observed WM changes likely contribute to long-term clinical deficits of posterior fossa tumour survivors.