Biological variation is ubiquitous in nature. Despite highly standardized breeding and husbandry under controlled environmental conditions, phenotypic diversity exists in laboratory mice and rats just as it does in humans. The resulting inter-individual variability affects various characteristics of animal disease models, including the responsiveness to drugs. Thus, the common practice of averaging data within an experimental group can lead to misinterpretations in neuroscience and other research fields. In this commentary, the impact of inter-individual variation in drug responsiveness is illustrated by examples from the testing of antiseizure medications in rodent temporal lobe epilepsy models. Individual mice and rats rendered epileptic by treatment according to standardized protocols fall into groups that either do or do not respond to antiseizure medications, thus mimicking the clinical situation in patients with epilepsy. Population responses are not normally distributed, and divergent responding is ...

Alpha-synuclein has been implicated in neurodegenerative diseases such as Parkinson's disease and dementia with Lewy bodies, with A53T and A30P mutations shown to be disease causing. It has been reported that hemizygous transgenic mice with tyrosine hydroxylase promotor-driven expression of A53T/A30P mutant alpha-synuclein in dopamine neurons provide a useful preclinical model of these conditions by virtue of developing behavioral deficits. Here, we report a lack of replication of this finding. Despite detecting robust overexpression of A53T/A30P mutant alpha-synuclein in dopamine neurons, we did not observe decreased tyrosine hydroxylase immunofluorescence or behavioral deficits in these mice. Our results demonstrate that preclinical models of synucleinopathy need careful validation in the field.

The paraventricular thalamic nucleus (PVT) is a brain region that mediates aversive and reward-related behaviors as shown in animals exposed to fear conditioning, natural rewards, or drugs of abuse. However, it is unknown whether manipulations of the PVT, in the absence of external factors or stimuli (e.g., fear, natural rewards, or drugs of abuse), are sufficient to drive reward-related behaviors. Additionally, it is unknown whether drugs of abuse administered directly into the PVT are sufficient to drive reward-related behaviors. Here, using behavioral as well as pathway and cell-type specific approaches, we manipulate PVT activity as well as the PVT-to-nucleus accumbens shell (NAcSh) neurocircuit to explore reward phenotypes. First, we show that bath perfusion of morphine (10 µm) caused hyperpolarization of the resting membrane potential, increased rheobase, and decreased intrinsic membrane excitability in PVT neurons that project to the NAcSh. Additionally, we found that direct injections of morphine (...

Content-to-context binding is crucial for working memory performance. Using a dual-serial retrocueing (DSR) task on oriented gratings, [Yu et al. (2020)][1] found that content (orientation) of both prioritized and unprioritized memory items (PMI; UMI) was represented simultaneously in visual cortex, while their context (location) was represented in intraparietal sulcus (IPS), with a priority-based remapping of the representation of content and context of the UMI in each region, respectively. This registered report acquired fMRI of 24 healthy adults while they performed a DSR task with location as the to-be-reported content and orientation as the task-relevant context. We contrasted three accounts: domain-dependent, the engagement of visual and parietal regions depends on the feature domain (orientation vs location); functional, the engagement of these regions depends on their function (content vs context); and hybrid—a combination of the domain-dependent account and the additional stipulation that IPS enco...

We often need to decide whether the object we look at is also the object we look for. When we look for one specific object, this process can be facilitated by feature-based attention. However, when we look for many objects at the same time (e.g., the products on our shopping list), such a strategy may no longer be possible, as research has shown that we can actively prepare to detect only one or two objects at a time. Therefore, looking for multiple objects additionally requires long-term memory search, slowing down decision-making. Interestingly, however, previous research has shown that distractor objects can be efficiently rejected during memory search when they are from a different category than the items in the memory set. Here, using EEG, we show that this efficiency is supported by top-down attention at the category level. In Experiment 1, human participants (both sexes) performed a memory search task on individually presented objects from different categories, most of which were distractors. We obs...

Tactile discrimination has been extensively studied, but mechanical pain discrimination remains poorly characterized. Here, we measured the capacity for mechanical pain discrimination using a two-alternative forced choice paradigm, with force-calibrated indentation stimuli (Semmes–Weinstein monofilaments) applied to the hand and foot dorsa of healthy human volunteers. In order to characterize the relationship between peripheral nociceptor activity and pain perception, we recorded single-unit activity from myelinated (A) and unmyelinated (C) mechanosensitive nociceptors in the skin using microneurography. At the perceptual level, we found that the foot was better at discriminating noxious forces than the hand, which stands in contrast to that for innocuous force discrimination, where the hand performed better than the foot. This observation of superior mechanical pain discrimination on the foot compared to the hand could not be explained by the responsiveness of individual nociceptors. We found no significa...

Learning and adaptation during sources of threat and safety are critical mechanisms for survival. The prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) have been broadly implicated in the processing of threat and safety. However, how these regions regulate threat and safety during naturalistic conditions involving thermal challenge still remains elusive. To examine this issue, we developed a novel paradigm in which adult mice learned that a particular zone that was identified with visuospatial cues was associated with either a noxious cold temperature (“threat zone”) or a pleasant warm temperature (“safety zone”). This led to the rapid development of avoidance behavior when the zone was paired with cold threat or approach behavior when the zone was paired with warm safety. During a long-term test without further thermal reinforcement, mice continued to exhibit robust avoidance or approach to the zone of interest, indicating that enduring spatial-based memories were forme...

A current hypothesis to explain the limited recovery following brain and spinal cord trauma stems from the dogma that neurons in the mammalian central nervous system lack the ability to regenerate their axons after injury. Serotonin (5-HT) neurons in the adult brain are a notable exception in that they can slowly regrow their axons following chemical or mechanical lesions. This process of regrowth occurs without intervention over several months and results in anatomical recovery that approximates the preinjured state. During development, serotonin is a trophic factor, playing a role in both cell survival and axon growth. Additionally, some studies have shown that stroke patients treated after injury with serotonin selective reuptake inhibitors (SSRIs) appeared to have improved recovery. To test the hypothesis that serotonin can influence the regrowth of 5-HT axons, mice received a high dose of para -chloroamphetamine (PCA) to induce widespread retrograde degeneration of 5-HT axons. Then, after a short rest...

Spinal cord injury (SCI) has become one of the common and serious diseases affecting patients’ motor functions. The small extracellular vesicles secreted by bone marrow mesenchymal stem cells (BMSCs) have shown a promising prospect for the treatment of neurological diseases. BMSCs were collected from rat bones. Osteogenic and adipogenic differentiation of BMSCs was further determined. Small extracellular vesicles were obtained by high-speed centrifugation. Dual-luciferase reporter assay was performed to demonstrate the targeting of miR-211-5p to the cyclooxygenase 2 (COX2) mRNA. qRT-PCR and Western blot assay were used for the detection of the mRNA and protein expression. ELISA was performed to estimate the levels of proinflammatory factors in spinal cord tissues. Our results showed that miR-211-5p targeted COX2 mRNA and regulated the protein expression of COX2 in BMSCs. Extracellular vesicles released from miR-211-5p-overexpressed BMSCs ameliorated SCI-induced motor dysfunction and motor evoked potential ...

In the article “Asymmetric Voltage Attenuation in Dendrites Can Enable Hierarchical Heterosynaptic Plasticity,” by Toviah Moldwin, Menachem Kalmenson, and Idan Segev, which was published online on …