Impaired Associative Learning Research Articles

Gordon Holmes Syndrome Model Mice Exhibit Alterations in Microglia, Age, and Sex-Specific Disruptions in Cognitive and Proprioceptive Function.

Gordon Holmes syndrome (GHS) is a neurological disorder associated with neuroendocrine, cognitive, and motor impairments with corresponding neurodegeneration. Mutations in the E3 ubiquitin ligase RNF216 are strongly linked to GHS. Previous studies show that deletion of Rnf216 in mice led to sex-specific neuroendocrine dysfunction due to disruptions in the hypothalamic-pituitary-gonadal axis. To address RNF216 action in cognitive and motor functions, we tested Rnf216 knock-out (KO) mice in a battery of motor and learning tasks for a duration of 1 year. Although male and female KO mice did not demonstrate prominent motor phenotypes, KO females displayed abnormal limb clasping. KO mice also showed age-dependent strategy and associative learning impairments with sex-dependent alterations of microglia in the hippocampus and cortex. Additionally, KO males but not females had more negative resting membrane potentials in the CA1 hippocampus without any changes in miniature excitatory postsynaptic current (mEPSC) frequencies or amplitudes. Our findings show that constitutive deletion of Rnf216 alters microglia and neuronal excitability, which may provide insights into the etiology of sex-specific impairments in GHS.

High temperatures during early development reduce adult cognitive performance and reproductive success in a wild animal population

Global warming is rapidly changing the phenology, distribution, behaviour and demography of wild animal populations. Recent studies in wild animals have shown that high temperatures can induce short-term cognitive impairment, and captive studies have demonstrated that heat exposure during early development can lead to long-term cognitive impairment. Given that cognition underpins behavioural flexibility and can be directly linked to fitness, understanding how high temperatures during early life might impact adult cognitive performance in wild animals is a critical next step to predict wildlife responses to climate change. Here, we investigated the relationship between temperatures experienced during development, adult cognitive performance, and reproductive success in wild southern pied babblers (Turdoides bicolor). We found that higher mean daily maximum temperatures during nestling development led to long-term cognitive impairment in associative learning performance, but not reversal learning performance. Additionally, a higher number of hot days (exceeding 35.5 °C, temperature threshold at which foraging efficiency and offspring provisioning decline) during post-fledging care led to reduced reproductive success in adulthood. We did not find evidence that low reproductive success was linked to impaired associative learning performance: associative learning performance was not related to reproductive success. In contrast, reversal learning performance was negatively related to reproductive success in breeding adults. This suggests that reproduction can carry a cost in terms of reduced performance in cognitively demanding tasks, confirming previous evidence in this species. Taken together, these findings indicate that naturally occurring high temperatures during early development have long-term negative effects on cognition and reproductive success in wild animals. Compounding effects of high temperatures on current nestling mortality and on the long-term cognitive and reproductive performance of survivors are highly concerning given ongoing global warming.

Reduced Implicit but not Explicit Knowledge of Cross-Situational Statistical Learning in Developmental Dyslexia.

Although statistical learning (SL) has been studied extensively in developmental dyslexia (DD), less attention has been paid to other fundamental challenges in language acquisition, such as cross-situational word learning. Such investigation is important for determining whether and how SL processes are affected in DD at the word level. In this study, typically developed (TD) adults and young adults with DD were exposed to a set of trials that contained multiple spoken words and multiple pictures of individual objects, with no information about word-referent correspondences provided within a trial. Nonetheless, cross-trial statistical relations could be exploited to learn word-referent mappings. The degree of within-trial reference uncertainty and the novelty of to-be-learned objects (novel or familiar) were varied under different learning conditions. The results show that across all conditions, young adults with DD were significantly impaired in their ability to exploit cross-trial regularities in co-occurring visual-auditory streams to discover word-referent mappings. Observed impairments were most pronounced when within-trial reference uncertainty was the highest. Subjective measures of knowledge awareness revealed greater development of implicit but not explicit knowledge in the TD group than in the DD group. Together, these findings suggest that the SL deficit in DD affects fundamental language learning challenges at the word level and points to greater reliance on explicit processes due to impaired implicit associative learning among individuals with DD. Such a deficit is likely to influence spoken language acquisition, and in turn affect literacy skills, in people with DD.

Liraglutide restores impaired associative learning in individuals with obesity

Survival under selective pressure is driven by the ability of our brain to use sensory information to our advantage to control physiological needs. To that end, neural circuits receive and integrate external environmental cues and internal metabolic signals to form learned sensory associations, consequently motivating and adapting our behaviour. The dopaminergic midbrain plays a crucial role in learning adaptive behaviour and is particularly sensitive to peripheral metabolic signals, including intestinal peptides, such as glucagon-like peptide 1 (GLP-1). In a single-blinded, randomized, controlled, crossover basic human functional magnetic resonance imaging study relying on a computational model of the adaptive learning process underlying behavioural responses, we show that adaptive learning is reduced when metabolic sensing is impaired in obesity, as indexed by reduced insulin sensitivity (participants: N = 30 with normal insulin sensitivity; N = 24 with impaired insulin sensitivity). Treatment with the GLP-1 receptor agonist liraglutide normalizes impaired learning of sensory associations in men and women with obesity. Collectively, our findings reveal that GLP-1 receptor activation modulates associative learning in people with obesity via its central effects within the mesoaccumbens pathway. These findings provide evidence for how metabolic signals can act as neuromodulators to adapt our behaviour to our body’s internal state and how GLP-1 receptor agonists work in clinics.

Restoration of brain dystrophin using tricyclo-DNA ASOs restores neurobehavioral deficits in DMD mice

Restoration of brain dystrophin using tricyclo-DNA ASOs restores neurobehavioral deficits in DMD mice

Protective effects of ginsenosides Rg1 and Rb1 against cognitive impairment induced by simulated microgravity in rats.

Microgravity experienced during space flight is known to exert several negative effects on the learning ability and memory of astronauts. Few effective strategies are currently available to counteract these effects. Rg1 and Rb1, the major steroidal components of ginseng, have shown potent neuroprotective effects with a high safety profile. The present study aimed to investigate the effects of Rg1 and Rb1 on simulated microgravity-induced learning and memory dysfunction and its underlying mechanism in the hindlimb suspension (HLS) rat model. Administration of Rg1 (30 and 60μmol/kg) and Rb1 (30 and 60μmol/kg) for 2weeks resulted in a significant amelioration of impaired spatial and associative learning and memory caused by 4-week HLS exposure, measured using the Morris water maze and Reward operating conditioning reflex (ROCR) tests, respectively. Furthermore, Rg1 and Rb1 administration alleviated reactive oxygen species production and enhanced antioxidant enzyme activities in the prefrontal cortex (PFC). Rg1 and Rb1 also assisted in the recovery of mitochondrial complex I (NADH dehydrogenase) activities, increased the expression of Mfn2 and decreased the fission marker dynamin-related protein (Drp)-1expression. Additionally, Rg1 and Rb1 treatment increased the SYN, and PSD95 protein expressions and decreased the ratio of Bax:Bcl-2 and reduced the expression of cleaved caspase-3 and cytochrome C. Besides these, the BDNF-TrkB/PI3K-Akt pathway was also activated by Rg1 and Rb1 treatment. Altogether, Rg1 and Rb1 treatment attenuated cognitive deficits induced by HLS, mitigated mitochondrial dysfunction, attenuated oxidative stress, inhibited apoptosis, increased synaptic plasticity, and restored BDNF-TrkB/PI3K-Akt signaling.

Partial restoration of brain dystrophin by tricyclo-DNA antisense oligonucleotides alleviates emotional deficits in mdx52 mice

The mdx52 mouse model recapitulates a frequent mutation profile associated with brain involvement in Duchenne muscular dystrophy. Deletion of exon 52 impedes expression of two dystrophins (Dp427, Dp140) expressed in brain, and is eligible for therapeutic exon-skipping strategies. We previously showed that mdx52 mice display enhanced anxiety and fearfulness, and impaired associative fear learning. In this study, we examined the reversibility of these phenotypes using exon 51 skipping to restore exclusively Dp427 expression in the brain of mdx52 mice. We first show that a single intracerebroventricular administration of tricyclo-DNA antisense oligonucleotides targeting exon 51 restores 5%-15% of dystrophin protein expression in the hippocampus, cerebellum, and cortex, at stable levels between 7 and 11week after injection. Anxiety and unconditioned fear were significantly reduced in treated mdx52 mice and acquisition of fear conditioning appeared fully rescued, while fear memory tested 24h later was only partially improved. Additional restoration of Dp427 in skeletal and cardiac muscles by systemic treatment did not further improve the unconditioned fear response, confirming the central origin of this phenotype. These findings indicate that some emotional and cognitive deficits associated with dystrophin deficiency may be reversible or at least improved by partial postnatal dystrophin rescue.

Neuronal deletion of CaV1.2 is associated with sex-specific behavioral phenotypes in mice

The gene CACNA1C, which encodes the pore forming subunit of the L-type calcium channel CaV1.2, is associated with increased risk for neuropsychiatric disorders including schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. Previous rodent work identified that loss or reduction of CaV1.2 results in cognitive, affective, and motor deficits. Most previous work has either included non-neuronal cell populations (haploinsufficient and Nestin-Cre) or investigated a discrete neuronal cell population (e.g. CaMKII-Cre, Drd1-Cre), but few studies have examined the effects of more broad neuron-specific deletion of CaV1.2. Additionally, most of these studies did not evaluate for sex-specific effects or used only male animals. Here, we sought to clarify whether there are sex-specific behavioral consequences of neuron-specific deletion of CaV1.2 (neuronal CaV1.2 cKO) using Syn1-Cre-mediated conditional deletion. We found that neuronal CaV1.2 cKO mice have normal baseline locomotor function but female cKO mice display impaired motor performance learning. Male neuronal CaV1.2 cKO display impaired startle response with intact pre-pulse inhibition. Male neuronal CaV1.2 cKO mice did not display normal social preference, whereas female neuronal CaV1.2 cKO mice did. Neuronal CaV1.2 cKO mice displayed impaired associative learning in both sexes, as well as normal anxiety-like behavior and hedonic capacity. We conclude that deletion of neuronal CaV1.2 alters motor performance, acoustic startle reflex, and social behaviors in a sex-specific manner, while associative learning deficits generalize across sexes. Our data provide evidence for both sex-specific and sex-independent phenotypes related to neuronal expression of CaV1.2.

Associative learning impairments in rats lacking dopamine transporter

Introduction. Changes in the expression of the dopamine transporter (DAT) have been identified in patients with a number of neuropsychiatric disorders, but their significance for pathogenesis remains unclear. DAT knockout rats are a promising model of frontostriatal dysfunctions involved in adapting learning processes to current organism's needs, motivation, and experience.The objective was to evaluate the effect of DAT disruption on the interaction of classical and instrumental conditioning processes (associative learning).Methods and materials. Rats from a local colony were used: knockouts (n=31), heterozygotes (n=32), and wild type rats (n=24). DAT knockout (Slc6a3) was detected by PCR followed by restriction analysis. The rats were kept individually with limited access to food and unlimited access to water. In the operant chambers equipped with a MED-PC interface (MED Associates, USA), 3 experiments were performed: 1) classical conditioning; 2) autoshaping of operant responding; 3) reward learning based on secondary reinforcement. Statistical analysis was performed using SigmaPlot 12.5 (Systat Software Inc., USA) and SPSS Statistics 21 (IBM, USA).Results. We revealed that DAT disruption in rats did not affect the formation of conditioned reflex connections in classical conditioning (1) but was accompanied by impairments in the autoshaping of the operant response (2) and learning based on secondary reinforcement (3).Conclusion. The observed impairments of associative learning might be associated with a decreased incentive value of stimuli in hyperdopaminergic state.

Outcome-Locked Cholinergic Signaling Suppresses Prefrontal Encoding of Stimulus Associations.

Acetylcholine (ACh) is thought to control arousal, attention, and learning by slowly modulating cortical excitability and plasticity. Recent studies, however, discovered that cholinergic neurons emit precisely timed signals about the aversive outcome at millisecond precision. To investigate the functional relevance of such phasic cholinergic signaling, we manipulated and monitored cholinergic terminals in the mPFC while male mice associated a neutral conditioned stimulus (CS) with mildly aversive eyelid shock (US) over a short temporal gap. Optogenetic inhibition of cholinergic terminals during the US promoted the formation of the CS-US association. On the contrary, optogenetic excitation of cholinergic terminals during the US blocked the association formation. The bidirectional behavioral effects paralleled the corresponding change in the expression of an activity-regulated gene, c-Fos in the mPFC. In contrast, optogenetic inhibition of cholinergic terminals during the CS impaired associative learning, whereas their excitation had marginal effects. In parallel, photometric recording from cholinergic terminals in the mPFC revealed strong innate phasic responses to the US. With subsequent CS-US pairings, cholinergic terminals weakened the responses to the US while developing strong responses to the CS. The across-session changes in the CS- and US-evoked terminal responses were correlated with associative memory strength. These findings suggest that phasic cholinergic signaling in the mPFC exerts opposite effects on aversive associative learning depending on whether it is emitted by the outcome or the cue.SIGNIFICANCE STATEMENT Drugs compensating for the decline of acetylcholine (ACh) are used for cognitive impairment, such as Alzheimer's disease. However, their beneficial effects are limited, demanding new strategies based on better understandings of how ACh modulates cognition. Here, we report that by manipulating ACh signals in the mPFC, we can control the strength of aversive associative learning in mice. Specifically, the suppression of ACh signals during an aversive outcome facilitated its association with a preceding cue. In contrast, the suppression of ACh signals during the cue impaired learning. Considering that this paradigm depends on the brain regions affected in Alzheimer's disease, our findings indicate that precisely timed control of ACh signals is essential to refine ACh-based strategies for cognitive enhancement.

The Lack of Dopamine Transporter Is Associated With Conditional Associative Learning Impairments and Striatal Proteomic Changes.

Dopamine (DA) is critically involved in different functions of the central nervous system (CNS) including control of voluntary movement, affect, reward, sleep, and cognition. One of the key components of DA neurotransmission is DA reuptake by the DA transporter (DAT), ensuring rapid clearance of DA from the synaptic cleft. Thus, lack of DAT leads to persistent high extracellular DA levels. While there is strong evidence for a role of striatal dopaminergic activity in learning and memory processes, little is known about the contribution of DAT deficiency to conditional learning impairments and underlying molecular processes. DAT-knockout (DAT-KO) rats were tested in a set of behavioral experiments evaluating conditional associative learning, which requires unaltered striatal function. In parallel, a large-scale proteomic analysis of the striatum was performed to identify molecular factors probably underlying behavioral patterns. DAT-KO rats were incapable to acquire a new operant skill in Pavlovian/instrumental autoshaping, although the conditional stimulus–unconditional stimulus (CS-US) association seems to be unaffected. These findings suggest that DAT directly or indirectly contributes to the reduction of transference of incentive salience from the reward to the CS. We propose that specific impairment of conditional learning might be caused by molecular adaptations to the hyperdopaminergic state, presumably by dopamine receptor 1 (DRD1) hypofunction, as proposed by proteomic analysis. Whether DRD1 downregulation can cause cognitive deficits in the hyperdopaminergic state is the subject of discussion, and further studies are needed to answer this question. This study may be useful for the interpretation of previous and the design of future studies in the dopamine field.

So what'cha want? The impact of individualised rewards on associative learning in psychopathic offenders

Psychopathic individuals typically present with associative learning impairments under explicit learning conditions. The present study aimed to investigate whether the formation of stimulus-outcome associations, as well as updating of these associations after changed contingencies, could be improved by using rewards with sufficiently high subjective values. To this end, 20 psychopathic offenders, 17 non-psychopathic offenders and 18 healthy controls performed a passive avoidance task with a reversal phase under three motivational conditions, using naturalistic rewards. The subjective values of the rewards were assessed a priori for each individual participant using a visual analogue scale. The correspondence of these values to their internal representation was confirmed by analyses of brain potentials. Analyses using both signal detection theory and classical approaches indicated that psychopathic offenders performed worse compared to the other groups during passive avoidance learning. However, using the signal detection approach, we found this deficiency to be present only when a hypothetical reward was used (‘neutral reward’ condition), whereas psychopathic offenders performed similar to the other groups when naturalistic rewards could be obtained (‘low reward’ and ‘high reward’ conditions). Furthermore, traditional analyses suggested that psychopathic offenders had more hits than the other groups during reversal learning, but the signal detection approach indicated that no effects of group or condition were present. Analysis of win-stay and lose-shift behaviour showed that psychopathic offenders were less likely to stay with a rewarded response during passive avoidance learning in the neutral reward condition. In addition, regardless of experimental phase or condition, psychopathic offenders were less likely to stop responding to a particular stimulus after receiving negative feedback. Although the approaches employed did not lead to unequivocal results, our findings suggest that psychopathic offenders do have the ability to adapt their behaviour to environmental contingencies when positive reinforcers with sufficiently high subjective values are used.

Deletion of the voltage-gated calcium channel, CaV 1.3, causes deficits in motor performance and associative learning.

L-type voltage-gated calcium channels are important regulators of neuronal activity and are widely expressed throughout the brain. One of the major L-type voltage-gated calcium channel isoforms in the brain is CaV 1.3. Mice lacking CaV 1.3 are reported to have impairments in fear conditioning and depressive-like behaviors, which have been linked to CaV 1.3 function in the hippocampus and amygdala. Genetic variation in CaV 1.3 has been linked to a variety of psychiatric disorders, including autism and schizophrenia, which are associated with altered motor learning, associative learning and social function. Here, we explored whether CaV 1.3 plays a role in these behaviors. We found that CaV 1.3 knockout mice have deficits in rotarod learning despite normal locomotor function. Deletion of CaV 1.3 is also associated with impaired gait adaptation and associative learning on the Erasmus Ladder. We did not observe any impairments in CaV 1.3 knockout mice on assays of anxiety-like, depression-like or social preference behaviors. Our results suggest an important role for CaV 1.3 in neural circuits involved in motor learning and concur with previous data showing its involvement in associative learning.

Disrupted Mitochondrial Network Drives Deficits of Learning and Memory in a Mouse Model of FOXP1 Haploinsufficiency.

Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate intellectual disability. Strongly reduced Foxp1 expression has been detected in the hippocampus of Foxp1+/− mice, a brain region required for learning and memory. To investigate learning and memory performance in these animals, fear conditioning tests were carried out, which showed impaired associative learning compared with wild type (WT) animals. To shed light on the underlying mechanism, we analyzed various components of the mitochondrial network in the hippocampus. Several proteins regulating mitochondrial biogenesis (e.g., Foxo1, Pgc-1α, Tfam) and dynamics (Mfn1, Opa1, Drp1 and Fis1) were significantly dysregulated, which may explain the increased mitophagy observed in the Foxp1+/− hippocampus. The reduced activity of complex I and decreased expression of Sod2 most likely increase the production of reactive oxygen species and the expression of the pre-apoptotic proteins Bcl-2 and Bax in this tissue. In conclusion, we provide evidence that a disrupted mitochondrial network and the resulting oxidative stress in the hippocampus contribute to the altered learning and cognitive impairment in Foxp1+/− mice, suggesting that similar alterations also play a major role in patients with FOXP1 syndrome.

Loosening of Associations in Chronic Schizophrenia: Intersectionality of Verbal Learning, Negative Symptoms, and Brain Structure.

In 1908, Bleuler proposed a unitary theory of schizophrenia, hypothesizing a “loosening of associations” as the central mechanism underlying disturbances in thinking, motivation, and affective expression. Here, we test Bleuler’s model in an archival sample of 79 healthy controls and 76 patients with chronic schizophrenia who had completed neuropsychological tests, including a measure of learning of novel word pairs, which was specifically selected to probe the structure and formation of new verbal associations. The patients also had positive and negative symptoms ratings, including measures of flat affect, anhedonia, and thought disorder. A subset of patients and controls (n = 39) had available prior archival 3-T magnetic resonance imaging (MRI) measures of prefrontal cortex (PFC) gray matter volumes. In relation to controls, patients showed evidence of a selective impairment in associative learning, independent of their overall reduced neuropsychological functioning. This neuropsychological impairment, in turn, correlated significantly with overall levels of negative but not positive symptoms, with the data showing an especially strong contribution of flattened emotional expression to verbal associate learning deficits in this patient sample. Moreover, the archival MRI data were consistent with prior research pointing to an important role of the PFC in supporting verbal associate learning and memory in patients and controls. Taken together, the current results provided evidence of a selective impairment in schizophrenia on a PFC-supported verbal associate learning and memory task, which was accompanied by negative symptoms in general, and flattened emotional expression, in particular.

Brain Expression, Physiological Regulation and Role in Motivation and Associative Learning of Peroxisome Proliferator-activated Receptor γ

Like other members of the superfamily of nuclear receptors, the peroxisome proliferator-activated receptor γ (PPARγ), is a ligand-activated transcription factor known for its insulin-sensitizing actions in the periphery. Despite only sparse evidence for PPARγ in the CNS, many reports suggest direct PPARγ-mediated actions in the brain. This study aimed to (i) map PPARγ expression in rodent brain areas, involved in the regulation of cognitive, motivational, and emotional functions, (ii) examine the regulation of central PPARγ by physiological variables (age, sex, obesity); (iii) chemotypically identify PPARγ-expressing cells in the frontal cortex (FC) and hippocampus (HP); (iv) study whether activation of PPARγ by pioglitazone (Pio) in FC and HP cells can induce target gene expression; and (v) demonstrate the impact of activated PPARγ on learning behavior and motivation. Immunoreactive PPARγ was detectable in specific sub-nuclei/subfields of the FC, HP, nucleus accumbens, amygdala, hypothalamus, thalamus, and granular layers of the cerebellum. PPARγ protein levels were upregulated during aging and in high fat diet-induced obesity. PPARγ mRNA expression was upregulated in the amygdala of females (but not males) that were made obese. Neural precursor cells, mature neurons, and astrocytes in primary FC and HP cultures were shown to express PPARγ. Pioglitazone dose-dependently upregulated PPARγ target genes in manner that was specific to the origin (FC or HP) of the cultures. Lastly, administration of Pio impaired motivation and associative learning. Collectively, we provide evidence for the presence of regulatable PPARγ in the brain and demonstrate their participation the regulation of key behaviors.

Repetitive Mild Traumatic Brain Injury in Rats Impairs Cognition, Enhances Prefrontal Cortex Neuronal Activity, and Reduces Pre-synaptic Mitochondrial Function.

A major hurdle preventing effective interventions for patients with mild traumatic brain injury (mTBI) is the lack of known mechanisms for the long-term cognitive impairment that follows mTBI. The closed head impact model of repeated engineered rotational acceleration (rCHIMERA), a non-surgical animal model of repeated mTBI (rmTBI), mimics key features of rmTBI in humans. Using the rCHIMERA in rats, this study was designed to characterize rmTBI-induced behavioral disruption, underlying electrophysiological changes in the medial prefrontal cortex (mPFC), and associated mitochondrial dysfunction. Rats received 6 closed-head impacts over 2 days at 2 Joules of energy. Behavioral testing included automated analysis of behavior in open field and home-cage environments, rotarod test for motor skills, novel object recognition, and fear conditioning. Following rmTBI, rats spent less time grooming and less time in the center of the open field arena. Rats in their home cage had reduced inactivity time 1 week after mTBI and increased exploration time 1 month after injury. Impaired associative fear learning and memory in fear conditioning test, and reduced short-term memory in novel object recognition test were found 4 weeks after rmTBI. Single-unit in vivo recordings showed increased neuronal activity in the mPFC after rmTBI, partially attributable to neuronal disinhibition from reduced inhibitory synaptic transmission, possibly secondary to impaired mitochondrial function. These findings help validate this rat rmTBI model as replicating clinical features, and point to impaired mitochondrial functions after injury as causing imbalanced synaptic transmission and consequent impaired long-term cognitive dysfunction.

Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice

The microtubule associated protein tau is an intrinsically disordered phosphoprotein that accumulates under pathological conditions leading to formation of neurofibrillary tangles, a hallmark of Alzheimer’s disease (AD). The mechanisms that initiate the accumulation of phospho-tau aggregates and filamentous deposits are largely unknown. In the past, our work and others’ have shown that molecular chaperones play a crucial role in maintaining protein homeostasis and that imbalance in their levels or activity can drive tau pathogenesis. We have found two co-chaperones of the 90 kDa heat shock protein (Hsp90), FK506-binding protein 52 (FKBP52) and the activator of Hsp90 ATPase homolog 1 (Aha1), promote tau aggregation in vitro and in the brains of tau transgenic mice. Based on this, we hypothesized that increased levels of these chaperones could promote tau misfolding and accumulation in the brains of aged wild-type mice. We tested this hypothesis by overexpressing Aha1, FKBP52, or mCherry (control) proteins in the hippocampus of 9-month-old wild-type mice. After 7 months of expression, mice were evaluated for cognitive and pathological changes. Our results show that FKBP52 overexpression impaired spatial reversal learning, while Aha1 overexpression impaired associative learning in aged wild-type mice. FKBP52 and Aha1 overexpression promoted phosphorylation of distinct AD-relevant tau species. Furthermore, FKBP52 activated gliosis and promoted neuronal loss leading to a reduction in hippocampal volume. Glial activation and phospho-tau accumulation were also detected in areas adjacent to the hippocampus, including the entorhinal cortex, suggesting that after initiation these pathologies can propagate through other brain regions. Overall, our findings suggest a role for chaperone imbalance in the initiation of tau accumulation in the aging brain.

Impulsivity and craving in subjects with opioid use disorder on methadone maintenance treatment

BackgroundMethadone maintenance treatment (MMT) is effective in decreasing opioid use or facilitating abstinence. Previous studies using small opioid use disorder samples suggest that cognitive impairments including impulsivity and executive functions may partially improve on MMT, but a range of deficits may persist. However, systematic assessments with larger samples are needed to confirm the profile of cognitive functions on MMT. MethodsWe assessed four types of impulsivity (delay discounting, reflection impulsivity, risk taking and motoric impulsivity), executive functioning (spatial working memory, paired associative learning and strategic planning) and drug cue-induced craving in a relatively large population (115 MMT patients, 115 healthy controls). The relationships between impulsivity, drug cue-induced craving and addiction-related variables were also assessed. ResultsDelay discounting, as well as drug cue-induced craving was increased in patients, while motoric impulsivity was lower than in controls. Paired associative learning was additionally impaired, which was explained by increased depression and anxiety levels in patients. Within the MMT group, the delay discounting and drug-cue induced craving scores were positively correlated with self-reported urgency, but unrelated to methadone dosage, duration on methadone, withdrawal symptoms, or presence of nicotine dependence. ConclusionsOur findings highlight increased delay discounting and cue-induced craving in MMT patients suggesting a potential role for trait effects in delay discounting. Although previous smaller studies have shown impaired executive function, in our large sample size on chronic MMT we only observed impaired associative learning related to depressive and anxiety symptoms highlighting a role for managing comorbid symptoms to further optimize cognitive function.

The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

HERC1 is a ubiquitin ligase protein, which, when mutated, induces several malformations and intellectual disability in humans. The animal model of HERC1 mutation is the mouse tambaleante characterized by: (1) overproduction of the protein; (2) cerebellar Purkinje cells death by autophagy; (3) dysregulation of autophagy in spinal cord motor neurons, and CA3 and neocortical pyramidal neurons; (4) impairment of associative learning, linked to altered spinogenesis and absence of LTP in the lateral amygdala; and, (5) motor impairment due to delayed action potential transmission, decrease synaptic transmission efficiency and altered myelination in the peripheral nervous system. To investigate the putative role of HERC1 in the presynaptic dynamics we have performed a series of experiments in cultured tambaleante hippocampal neurons by using transmission electron microscopy, FM1-43 destaining and immunocytochemistry. Our results show: (1) a decrease in the number of synaptic vesicles; (2) reduced active zones; (3) less clathrin immunoreactivity and less presynaptic endings over the hippocampal main dendritic trees; which contrast with (4) a greater number of endosomes and autophagosomes in the presynaptic endings of the tambaleante neurons relative to control ones. Altogether these results show an important role of HERC1 in the regulation of presynaptic membrane dynamics.