BDNF-dependent modulation of axonal transport is selectively impaired in ALS

Axonal transport ensures long-range delivery of essential cargoes between proximal and distal compartments of neurons, and is needed for neuronal development, function, and survival. Deficits in axonal transport have been detected at pre-symptomatic stages in mouse models of amyotrophic lateral sclerosis (ALS), suggesting that impairments are fundamental for disease pathogenesis. However, the precise mechanisms responsible for the transport deficits and whether they preferentially affect α-motor neuron (MN) subtypes remain unresolved. Here, we report that stimulation of wild-type neurons with brain-derived neurotrophic factor (BDNF) enhances trafficking of signalling endosomes specifically in fast MNs (FMNs). In early symptomatic SOD1G93A mice, FMNs display selective impairment of axonal transport and develop an insensitivity to BDNF stimulation, with pathology upregulating classical non-pro-survival receptors in muscles and sciatic nerves. Altogether, these data indicate that cell- and non-cell autonomous BDNF signalling is impaired in vulnerable SOD1G93A MNs, thus identifying a new key deficit in ALS amenable for future therapeutic interventions.

No evidence for embodiment: The motor system is not needed to keep action words in working memory

Increasing evidence implicates the sensorimotor systems with high-level cognition, but the extent to which these systems play a functional role remains debated. Using an elegant design, Shebani and Pulvermüller (2013) reported that carrying out a demanding rhythmic task with the hands led to selective impairment of working memory for hand-related words (e.g., clap), while carrying out the same task with the feet led to selective memory impairment for foot-related words (e.g., kick). Such a striking double dissociation is acknowledged even by critics to constitute strong evidence for an embodied account of working memory. Here, we report on an attempt at a direct replication of this important finding. We followed a sequential sampling design and stopped data collection at N=77 (more than five times the original sample size), at which point the evidence for the lack of the critical selective interference effect was very strong (BF01 = 91). This finding constitutes strong evidence against a functional contribution of the motor system to keeping action words in working memory. Our finding fits into the larger emerging picture in the field of embodied cognition that sensorimotor simulations are neither required nor automatic in high-level cognitive processes, but that they may play a role depending on the task. Importantly, we urge researchers to engage in transparent, high-powered, and fully pre-registered experiments like the present one to ensure the field advances on a solid basis.

Leaving the Door Open: Trauma, Updating, and the Development of PTSD Symptoms

Humans try to make sense of the world using hypotheses that were formed by prior experiences. After trauma, these hypotheses can be exaggerated and resistant to change. This may result in difficulties to update expectations regarding the negative outcomes associated with traumatic stimuli. Critically, it has been proposed that such difficulties may drive the development of posttraumatic stress disorder (PTSD). However, direct evidence on the associations between trauma and impaired expectation updating is still absent. Moreover, it remains unclear whether such an impairment is correlated with PTSD symptoms. To address these gaps, we compared the ability to update traumatic and neutral stimulus-outcome expectations in 81 active-duty firefighters. Participants completed a performance-based reversal learning task and were assessed for PTSD symptoms. We predicted and found a selective impairment in updating trauma-related expectations. This impairment was evident for negative-to-positive but not for positive-to-negative updating. Moreover, impaired negative-to-positive updating was positively associated with PTSD symptoms. These findings support the predictive processing account of PTSD and suggest that strengthening updating processes could be an important goal for promoting resilience after trauma.

Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice

Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality.

Escitalopram Restores Reversal Learning Impairments in Rats with Lesions of Orbital Frontal Cortex

The term ‘cognitive structures’ is used to describe the fact that mental models underlie thinking, reasoning and representing. Cognitive structures generally improve the efficiency of information processing by providing a situational framework within which there are parameters governing the nature and timing of information and appropriate responses can be anticipated. Unanticipated events that violate the parameters of the cognitive structure require the cognitive model to be updated, but this comes at an efficiency cost. In reversal learning a response that had been reinforced is no longer reinforced, while an alternative is now reinforced, having previously not been (A+/B− becomes A−/B+). Unanticipated changes of contingencies require that cognitive structures are updated. In this study, we examined the effect of lesions of the orbital frontal cortex (OFC) and the effects of the selective serotonin reuptake inhibitor (SSRI), escitalopram, on discrimination and reversal learning. Escitalopram was without effect in intact rats. Rats with OFC lesions had selective impairment of reversal learning, which was ameliorated by escitalopram. We conclude that reversal learning in OFC-lesioned rats is an easily administered and sensitive test that can detect effects of serotonergic modulation on cognitive structures that are involved in behavioural flexibility.