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There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities that are more pronounced in males than in females. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis., Competing Interests: Disclosure and competing interests statement The authors declare no competing interests., (© 2024. The Author(s).)

This review delves into the phenomenon of positive emotional contagion (PEC) in rodents, an area that remains relatively understudied compared to the well-explored realm of negative emotions such as fear or pain. Rodents exhibit clear preferences for individuals expressing positive emotions over neutral counterparts, underscoring the importance of detecting and responding to positive emotional signals from others. We thoroughly examine the adaptive function of PEC, highlighting its pivotal role in social learning and environmental adaptation. The developmental aspect of the ability to interpret positive emotions is explored, intricately linked to maternal care and social interactions, with oxytocin playing a central role in these processes. We discuss the potential involvement of the reward system and draw attention to persisting gaps in our understanding of the neural mechanisms governing PEC. Presenting a comprehensive overview of the existing literature, we focus on food-related protocols such as the Social Transmission of Food Preferences paradigm and tickling behaviour. Our review emphasizes the pressing need for further research to address lingering questions and advance our comprehension of positive emotional contagion., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The Wnt/β-catenin pathway contains multiple high-confidence risk genes that are linked to neurodevelopmental disorders, including autism spectrum disorder. However, its ubiquitous roles across brain cell types and developmental stages have made it challenging to define its impact on neural circuit development and behavior. Here, we show that TCF7L2, which is a key transcriptional effector of the Wnt/β-catenin pathway, plays a cell-autonomous role in postnatal astrocyte maturation and impacts adult social behavior. TCF7L2 was the dominant Wnt effector that was expressed in both mouse and human astrocytes, with a peak during astrocyte maturation. The conditional knockout of Tcf7l2 in postnatal astrocytes led to an enlargement of astrocytes with defective tiling and gap junction coupling. These mice also exhibited an increase in the number of cortical excitatory and inhibitory synapses and a marked increase in social interaction by adulthood. These data reveal an astrocytic role for developmental Wnt/β-catenin signaling in restricting excitatory synapse numbers and regulating adult social behavior., (© 2023. The Author(s).)

For social interaction to be successful, two conditions must be met: the motivation to initiate it and the ability to maintain it. This study uses both optogenetic and chemogenetic approaches to reveal the specific neural pathways that selectively influence those two social interaction components., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Rojek-Sito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Reading danger signals may save an animal's life, and learning about threats from others allows avoiding first-hand aversive and often fatal experiences. Fear expressed by other individuals, including those belonging to other species, may indicate the presence of a threat in the environment and is an important social cue. Humans and other animals respond to conspecifics' fear with increased activity of the amygdala, the brain structure crucial for detecting threats and mounting an appropriate response to them. It is unclear, however, whether the cross-species transmission of threat information involves similar mechanisms, e.g., whether animals respond to the aversively induced emotional arousal of humans with activation of fear-processing circuits in the brain. Here, we report that when rats interact with a human caregiver who had recently undergone fear conditioning, they show risk assessment behavior and enhanced amygdala activation. The amygdala response involves its two major parts, the basolateral and central, which detect a threat and orchestrate defensive responses. Further, we show that humans who learn about a threat by observing another aversively aroused human, similar to rats, activate the basolateral and centromedial parts of the amygdala. Our results demonstrate that rats detect the emotional arousal of recently aversively stimulated caregivers and suggest that cross-species social transmission of threat information may involve similar neural circuits in the amygdala as the within-species transmission.

Prediction error (PE) is the mismatch between a prior expectation and reality, and it lies at the core of associative learning about aversive and appetitive stimuli. Human studies on fear learning have linked the amygdala to aversive PEs. In contrast, the relationship between the amygdala and PE in appetitive settings and stimuli, unlike those that induce fear, has received less research attention. Animal studies show that the amygdala is a functionally heterogeneous structure. Nevertheless, the role of the amygdala nuclei in PE signaling remains unknown in humans. To clarify the role of two subdivisions of the human amygdala, the centromedial amygdala (CMA) and basolateral amygdala (BLA), in appetitive and aversive PE signaling, we used gustatory pavlovian learning involving eating-related naturalistic outcomes. Thirty-eight right-handed individuals (19 females) participated in the study. We found that surprise with neutral feedback when a reward is expected triggers activity within the left and right CMA. When an aversive outcome is expected, surprise with neutral feedback triggers activity only within the left CMA. Notably, the BLA was not activated by those conditions. Thus, the CMA engages in negative PE signaling during appetitive and aversive gustatory pavlovian learning, whereas the BLA is not critical for this process. In addition, PE-related activity within the left CMA during aversive learning is negatively correlated with neuroticism and positively correlated with extraversion. The findings indicate the importance of the CMA in gustatory learning when the value of outcomes changes and have implications for understanding psychological conditions that manifest perturbed processing of negative PEs. SIGNIFICANCE STATEMENT A discrepancy between a prediction and an actual outcome (PE) plays a crucial role in learning. Learning improves when an outcome is more significant than expected (positive PE) and worsens when it is smaller than expected (negative PE). We found that the negative PE during appetitive and aversive taste learning is associated with increased activity of the CMA, which suggests that the CMA controls taste learning. Our findings may have implications for understanding psychological states associated with deficient learning from negative PEs, such as obesity and addictive behaviors., (Copyright © 2023 Kolada et al.)

Social support during exposure-based psychotherapy is believed to diminish fear and improve therapy outcomes. However, some clinical trials challenge that notion. Underlying mechanisms remain unknown, hindering the understanding of benefits and pitfalls of such approach. To study social buffering during fear extinction, we developed a behavioral model in which partner's presence decreases response to fear-associated stimuli. To identify the neuronal background of this phenomenon, we combined behavioral testing with c-Fos mapping, optogenetics, and chemogenetics. We found that the presence of a partner during fear extinction training causes robust inhibition of freezing; the effect, however, disappears in subjects tested individually on the following day. It is accompanied by lowered activation of the prelimbic (PL) and anterior cingulate (ACC) but not infralimbic (IL) cortex. Accordingly, blocking of IL activity left social buffering intact. Similarly, inhibition of the ventral hippocampus-PL pathway, suppressing fear response after prolonged extinction training, did not diminish the effect. In contrast, inhibition of the ACC-central amygdala pathway, modulating social behavior, blocked social buffering. By reporting that social modulation of fear inhibition is transient and insensitive to manipulation of the fear extinction-related circuits, we show that the mechanisms underlying social buffering during extinction are different from those of individual extinction., (© The Author(s) 2022. Published by Oxford University Press.)

Humans often benefit from social cues when learning about the world. For instance, learning about threats from others can save the individual from dangerous first-hand experiences. Familiarity is believed to increase the effectiveness of social learning, but it is not clear whether it plays a role in learning about threats. Using functional magnetic resonance imaging, we undertook a naturalistic approach and investigated whether there was a difference between observational fear learning from friends and strangers. Participants (observers) witnessed either their friends or strangers (demonstrators) receiving aversive (shock) stimuli paired with colored squares (observational learning stage). Subsequently, participants watched the same squares, but without receiving any shocks (direct-expression stage). We observed a similar pattern of brain activity in both groups of observers. Regions related to threat responses (amygdala, anterior insula, anterior cingulate cortex) and social perception (fusiform gyrus, posterior superior temporal sulcus) were activated during the observational phase, possibly reflecting the emotional contagion process. The anterior insula and anterior cingulate cortex were also activated during the subsequent stage, indicating the expression of learned threat. Because there were no differences between participants observing friends and strangers, we argue that social threat learning is independent of the level of familiarity with the demonstrator., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

GluN2B is an NMDAR subunit that displays restricted expression in the mature hippocampus - a structure playing a major role in temporal lobe epilepsy. However, the contribution of GluN2B to the pathophysiology of the condition has not been fully explored. Here we combined status epilepticus models of temporal lobe epilepsy, protein expression studies, and patch-clamp experiments to demonstrate the profound change in the nature of glutamatergic transmission mediated in the epileptiform hippocampus by a subpopulation of GluN2B-containing NMDAR receptors. Satisfactory control of chronic seizures in temporal lobe epilepsy is still impossible for about 40% of patients. Therefore, new therapeutic approaches against the condition are desired. Using video-EEG recordings in animals and ex vivo extracellular recordings in brain sections, we present here the potential of ifenprodil (GluN2B selective NMDAR antagonist) for altering the course of epileptogenesis and ictogenesis in temporal lobe epilepsy. In sum, we identify GluN2B as one of the factors in the pathogenesis of recurrent seizures and provide a rationale for clinical studies on ifenprodil as a new candidate therapeutic against temporal lobe epilepsy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Empathy is critical to adjusting our behavior to the state of others. The past decade dramatically deepened our understanding of the biological origin of this capacity. We now understand that rodents robustly show emotional contagion for the distress of others via neural structures homologous to those involved in human empathy. Their propensity to approach others in distress strengthens this effect. Although rodents can also learn to favor behaviors that benefit others via structures overlapping with those of emotional contagion, they do so less reliably and more selectively. Together, this suggests evolution selected mechanisms for emotional contagion to prepare animals for dangers by using others as sentinels. Such shared emotions additionally can, under certain circumstances, promote prosocial behavior., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Until recently laboratory tasks for studying behavior were highly artificial, simplified, and designed without consideration for the environmental or social context. Although such an approach offers good control over behavior, it does not allow for researching either voluntary responses or individual differences. Importantly for neuroscience studies, the activity of the neural circuits involved in producing unnatural, artificial behavior is variable and hard to predict. In addition, different ensembles may be activated depending on the strategy the animal adopts to deal with the spurious problem. Thus, artificial and simplified tasks based on responses, which do not occur spontaneously entail problems with modeling behavioral impairments and underlying brain deficits. To develop valid models of human disorders we need to test spontaneous behaviors consistently engaging well-defined, evolutionarily conserved neuronal circuits. Such research focuses on behavioral patterns relevant for surviving and thriving under varying environmental conditions, which also enable high reproducibility across different testing settings., Competing Interests: The authors declare no competing financial interests in relation to the work described., (© 2022 The Authors.)

Translational value of mouse models of neuropsychiatric disorders depends heavily on the accuracy with which they replicate symptoms observed in the human population. In mouse models of autism spectrum disorder (ASD) these include, among others, social affiliation, and communication deficits as well as impairments in understanding and perception of others. Most studies addressing these issues in the BTBR T+ Itpr3tf/J mouse, an idiopathic model of ASD, were based on short dyadic interactions of often non-familiar partners placed in a novel environment. In such stressful and variable conditions, the reproducibility of the phenotype was low. Here, we compared physical conditions and the degree of habituation of mice at the time of testing in the three chambered social affiliation task, as well as parameters used to measure social deficits and found that both the level of stress and human bias profoundly affect the results of the test. To minimize these effects, we tested social preference and network dynamics in mice group-housed in the Eco-HAB system. This automated recording allowed for long-lasting monitoring of differences in social repertoire (including interest in social stimuli) in BTBR T+ Itpr3tf/J and normosocial c57BL/6J mice. With these observations we further validate the BTBR T+ Itpr3tf/J mouse as a model for ASD, but at the same time emphasize the need for more ecological testing of social behavior within all constructs of the Systems for Social Processes domain (as defined by the Research Domain Criteria framework)., (© 2022 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Alterations in social behavior are core symptoms of major developmental neuropsychiatric diseases such as autism spectrum disorders or schizophrenia. Hence, understanding their molecular and cellular underpinnings constitutes the major research task. Dysregulation of the global gene expression program in the developing brain leads to modifications in a number of neuronal connections, synaptic strength and shape, causing unbalanced neuronal plasticity, which may be important substrate in the pathogenesis of neurodevelopmental disorders, contributing to their clinical outcome. Serum response factor (SRF) is a major transcription factor in the brain. The behavioral influence of SRF deletion during neuronal differentiation and maturation has never been studied because previous attempts to knock-out the gene caused premature death. Herein, we generated mice that lacked SRF from early postnatal development to precisely investigate the role of SRF starting in the specific time window before maturation of excitatory synapses that are located on dendritic spine occurs. We show that the time-controlled loss of SRF in neurons alters specific aspects of social behaviors in SRF knock-out mice, and causes deficits in developmental spine maturation at both the structural and functional levels, including downregulated expression of the AMPARs subunits GluA1 and GluA2, and increases the percentage of filopodial/immature dendritic spines. In aggregate, our study uncovers the consequences of postnatal SRF elimination for spine maturation and social interactions revealing novel mechanisms underlying developmental neuropsychiatric diseases., (© 2022. The Author(s).)

The enlarged brains of homeotherms bring behavioural advantages, but also incur high energy expenditures. The 'expensive brain' (EB) hypothesis posits that the energetic costs of the enlarged brain and the resulting increased cognitive abilities (CA) were met by either increased energy turnover or reduced allocation to other expensive organs, such as the gut. We tested the EB hypothesis by analysing correlated responses to selection in an experimental evolution model system, which comprises line types of laboratory mice selected for high or low basal metabolic rate (BMR), maximum (VO 2max ) metabolic rates and random-bred (unselected) lines. The traits are implicated in the evolution of homeothermy, having been pre-requisites for the encephalization and exceptional CA of mammals, including humans. High-BMR mice had bigger guts, but not brains, than mice of other line types. Yet, they were superior in the cognitive tasks carried out in both reward and avoidance learning contexts and had higher neuronal plasticity (indexed as the long-term potentiation) than their counterparts. Our data indicate that the evolutionary increase of CA in mammals was initially associated with increased BMR and brain plasticity. It was also fuelled by an enlarged gut, which was not traded off for brain size.

In contrast to easily formed fear memories, fear extinction requires prolonged training. The prelimbic cortex (PL), which integrates signals from brain structures involved in fear conditioning and extinction such as the ventral hippocampus (vHIP) and the basolateral amygdala (BL), is necessary for fear memory retrieval. Little is known, however, about how the vHIP and BL inputs to the PL regulate the display of fear after fear extinction. Using functional anatomy tracing in male rats, we found two distinct subpopulations of neurons in the PL activated by either the successful extinction or the relapse of fear. During the retrieval of fear extinction memory, the dominant input to active neurons in the PL was from the vHIP, whereas the retrieval of fear memory, regardless of the age of a memory and testing context, was associated with greater BL input. Optogenetic stimulation of the vHIP-PL pathway after one session of fear extinction increased conditioned fear, whereas stimulation of the vHIP inputs after several sessions of extinction decreased the conditioned fear response. This latter effect was, however, transient, as stimulation of this pathway 28 d after extinction increased conditioned fear response again. The results show that repeated fear extinction training gradually changes vHIP-PL connectivity, making fear suppression possible, whereas in the absence of fear suppression from the vHIP, signals from the BL can play a dominant role, resulting in high levels of fear. SIGNIFICANCE STATEMENT Behavioral therapies of fear are based on extinction learning. As extinction memories fade over time, such therapies produce only a temporary suppression of fear, which constitutes a clinical and societal challenge. In our study, we provide a framework for understating the underlying mechanism by which extinction of fear memories fade by demonstrating the existence of two subpopulations of neurons in the prelimbic cortex associated with low and high levels of fear. Insufficient extinction and exposure to the context in which fear memory was formed promoted high fear neuronal activity in the prelimbic cortex, leading to fear retrieval. Extensive extinction training, on the other hand, boosted low fear neuronal activity and, as a result, extinction memory retrieval. This effect was, however, transient and disappeared with time., (Copyright © 2021 the authors.)

Ultrasonic vocalizations are among the oldest evolutionarily forms of animal communication. In order to study the communication patterns in an aversive social situation, we used a behavioral model in which one animal, the observer, is witnessing as his cagemate, the demonstrator, is experiencing a series of mild electrical foot shocks. We studied the effect of the foot shock experience on the observer and the influence of a warning sound (emitted shortly before the shock) on USV communication. These experiments revealed that such a warning seems to increase the arousal level, which differentiates the responses depending on previous experience. This can be identified by the emission of characteristic, short 22 kHz calls of a duration below 100 ms. Two rats emitted calls that overlapped in time. Analysis of these overlaps revealed that in 'warned' pairs with a naive observer, 22 kHz calls were mixed with 50 kHz calls. This fact, combined with a high fraction of very high-pitched 50 kHz calls (over 75 kHz), suggests the presence of the phenomenon of social buffering. Pure 22 kHz overlaps were mostly found in 'warned' pairs with an experienced observer, suggesting a possible fear contagion with distress sharing. The results show the importance of dividing 22 kHz calls into long and short categories.

Animals display a rich repertoire of defensive responses adequate to the threat proximity. In social species, these reactions can be additionally influenced by the behavior of fearful conspecifics. However, the majority of neuroscientific studies on socially triggered defensive responses focuses on one type of behavior, freezing. To study a broader range of socially triggered reactions and underlying mechanisms, we directly compared two experimental paradigms, mimicking occurrence of the imminent versus remote threat. Observation of a partner currently experiencing aversive stimulation evokes passive defensive responses in the observer rats. Similar interaction with a partner that has just undergone the aversive stimulation prompts animals to increase active exploration. Although the observers display behaviors similar to those of the aversively stimulated demonstrators, their reactions are not synchronized in time, suggesting that observers' responses are caused by the change in their affective state rather than mimicry. Using opsins targeted to behaviorally activated neurons, we tagged central amygdala (CeA) cells implicated in observers' responses to either imminent or remote threat and reactivated them during the exploration of a novel environment. The manipulation revealed that the two populations of CeA cells promote passive or active defensive responses, respectively. Further experiments confirmed that the two populations of cells at least partially differ in expression of molecular markers (protein kinase C-δ [PKC-δ] and corticotropin-releasing factor [CRF]) and connectivity patterns (receiving input from the basolateral amygdala or from the anterior insula). The results are consistent with the literature on single subjects' fear conditioning, suggesting that similar neuronal circuits control defensive responses in social and non-social contexts., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: The therapeutic effects of fluoxetine are believed to be due to increasing neuronal plasticity and reversing some learning deficits. Nevertheless, a growing amount of evidence shows adverse effects of this drug on cognition and some forms of neuronal plasticity., Experimental Approach: To study the effects of chronic fluoxetine treatment, we combine an automated assessment of motivation and learning in mice with an investigation of neuronal plasticity in the central amygdala and basolateral amygdala. We use immunohistochemistry to visualize neuronal types and perineuronal nets, along with DI staining to assess dendritic spine morphology. Gel zymography is used to test fluoxetine's impact on matrix metalloproteinase-9, an enzyme involved in synaptic plasticity., Key Results: We show that chronic fluoxetine treatment in non-stressed mice increases perineuronal nets-dependent plasticity in the basolateral amygdala, while impairing MMP-9-dependent plasticity in the central amygdala. Further, we illustrate how the latter contributes to anhedonia and deficits of reward learning. Behavioural impairments are accompanied by alterations in morphology of dendritic spines in the central amygdala towards an immature state, most likely reflecting animals' inability to adapt. We strengthen the link between the adverse effects of fluoxetine and its influence on MMP-9 by showing that behaviour of MMP-9 knockout animals remains unaffected by the drug., Conclusion and Implications: Chronic fluoxetine treatment differentially affects various forms of neuronal plasticity, possibly explaining its opposing effects on brain and behaviour. These findings are of immediate clinical relevance since reported side effects of fluoxetine pose a potential threat to patients., (© 2020 British Pharmacological Society.)

Learning to avoid threats often occurs by observing others. Most previous research on observational fear learning (OFL) in humans has used pre-recorded standardized video of an actor and thus lacked ecological validity. Here, we aimed to enhance ecological validity of the OFL by engaging participants in a real-time observational procedure (35 pairs of healthy male friends, age 18-27). One of the participants watched the other undergo a differential fear conditioning task, in which a conditioned stimulus (CS+) was paired with an aversive electric shock and another stimulus (CS-) was always safe. Subsequently, the CS+ and CS- were presented to the observer to test the OFL. While the friend's reactions to the shock elicited strong skin conductance responses (SCR) in all observers, subsequent differential SCRs (CS+ > CS-) were found only when declarative knowledge of the CS+/US contingency (rated by the participants) was acquired. Contingency-aware observers also showed elevated fear potentiated startle responses during both CS+ and CS- compared to baseline. We conclude that our real-time procedure can be effectively used to study OFL. The procedure allowed for dissecting two components of the OFL: an automatic emotional reaction to the response of the demonstrator and learning about stimulus contingency.

Synapses are the regions of the neuron that enable the transmission and propagation of action potentials on the cost of high energy consumption and elevated demand for mitochondrial ATP production. The rapid changes in local energetic requirements at dendritic spines imply the role of mitochondria in the maintenance of their homeostasis. Using global proteomic analysis supported with complementary experimental approaches, we show that an essential pool of mitochondrial proteins is locally produced at the synapse indicating that mitochondrial protein biogenesis takes place locally to maintain functional mitochondria in axons and dendrites. Furthermore, we show that stimulation of synaptoneurosomes induces the local synthesis of mitochondrial proteins that are transported to the mitochondria and incorporated into the protein supercomplexes of the respiratory chain. Importantly, in a mouse model of fragile X syndrome, Fmr1 KO mice, a common disease associated with dysregulation of synaptic protein synthesis, we observed altered morphology and respiration rates of synaptic mitochondria. That indicates that the local production of mitochondrial proteins plays an essential role in synaptic functions., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Since the 1980s, we have witnessed the rapid development of genetically modified mouse models of human diseases. A large number of transgenic and knockout mice have been utilized in basic and applied research, including models of neurodegenerative and neuropsychiatric disorders. To assess the biological function of mutated genes, modern techniques are critical to detect changes in behavioral phenotypes. We review the IntelliCage, a high-throughput system that is used for behavioral screening and detailed analyses of complex behaviors in mice. The IntelliCage was introduced almost two decades ago and has been used in over 150 studies to assess both spontaneous and cognitive behaviors. We present a critical analysis of experimental data that have been generated using this device., Competing Interests: Declaration of Competing Interest Prof. Hans-Peter Lipp developed the idea of the IntelliCage based on his original experiments. Prof. Lipp owns shares in NewBehavior Company. The system was initially marketed by NewBehavior GmbH (Zürich, Switzerland), which is now fully owned by TSE-Systems International (Frankfurt, Germany). Prof. Lipp owns a consulting company (Neurospex GmbH) that provides advice for IntelliCage users and also designs other neurobehavioral projects and is co-owner of XBehavior GmbH, a company that provides automated R-based analyses of IntelliCage and GPS tracking data and extended programming capacities for IntelliCage users., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Learning the value of stimuli and actions from others - social learning - adaptively contributes to individual survival and plays a key role in cultural evolution. We review research across species targeting the neural and computational systems of social learning in both the aversive and appetitive domains. Social learning generally follows the same principles as self-experienced value-based learning, including computations of prediction errors and is implemented in brain circuits activated across task domains together with regions processing social information. We integrate neural and computational perspectives of social learning with an understanding of behaviour of varying complexity, from basic threat avoidance to complex social learning strategies and cultural phenomena.

Social transfer of fear is a potent tool facilitating response to danger in animals forming social groups. With many factors influencing the transfer-such as proximity of the animal receiving information to the donor, familiarity, proximity of danger, and species-specific coping strategies-it allows studies of neuronal correlates of a variety of behavioral responses. Since both the transfer of fear and social modulation of fear responses are impaired in many neuropsychological disorders, the models described in this article could be useful in disentangling the neuronal circuitry involved in the pathogenesis of these disorders. © 2019 by John Wiley & Sons, Inc. Basic Protocol 1: Imminent threat in rats Alternate Protocol 1: Imminent threat in mice Basic Protocol 2: Remote threat in rats Alternate Protocol 2: Remote threat in mice Basic Protocol 3: Social modulation of fear extinction in rats Alternate Protocol 3: Social modulation of fear extinction in mice., (© 2019 John Wiley & Sons, Inc.)

TAR DNA-binding protein 43 (TDP-43) is a hallmark of some neurodegenerative disorders, such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. TDP-43-related pathology is characterized by its abnormally phosphorylated and ubiquitinated aggregates. It is involved in many aspects of RNA processing, including mRNA splicing, transport, and translation. However, its exact physiological function and role in mechanisms that lead to neuronal degeneration remain elusive. Transgenic rats that were characterized by TDP-43 depletion in neurons exhibited enhancement of the acquisition of fear memory. At the cellular level, TDP-43-depleted neurons exhibited a decrease in the short-term plasticity of intrinsic neuronal excitability. The induction of long-term potentiation in the CA3-CA1 areas of the hippocampus resulted in more stable synaptic enhancement. At the molecular level, the protein levels of an unedited (R) FLOP variant of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluR1 and GluR2/3 subunits decreased in the hippocampus. Alterations of FLOP/FLIP subunit composition affected AMPAR kinetics, reflected by cyclothiazide-dependent slowing of the decay time of AMPAR-mediated miniature excitatory postsynaptic currents. These findings suggest that TDP-43 may regulate activity-dependent neuronal plasticity, possibly by regulating the splicing of genes that are responsible for fast synaptic transmission and membrane potential., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Different rat and mouse models are used in studies of social interactions. Simple behavioral measures, which are commonly used in the laboratory, allow to perform relatively short experiments and to use multiple brain manipulation techniques. However, too much focus on the simplest behavioral models generates a serious risk of reducing ecological validity or even studying phenomena which would never happen outside of the laboratory. In this review, we discuss the suitability of mice and rats as model organisms for studying social behaviors, with focus on social transmission of fear paradigms. First, we briefly introduce the concept of domestication and what impact it had on laboratory rodents. Then, we present two aspects of social behaviors, sociability and dominance, which are crucial for social organization in these species. Finally, we present experimental models used for studying how animals transmit information about danger between each other, and how these models may reflect what happens in the natural environment. We discuss the difficulties that arise from our limited knowledge of rat and mouse ecology, especially their social life. We also explore the subject of balancing ecological validity and controllability in rodent models of social behaviors, the latter being particularly important for studying brain activity. Although it is very challenging, an efficient program for social neuroscience research should, in our opinion, aim at bridging the gap between laboratory and field studies., (© 2018 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

While many consider empathy an exclusively human trait, non-human animals are capable of simple forms of empathy, such as emotional contagion, as well as consolation and helping behavior. Rodent models are particularly useful for describing the neuronal background of these phenomena. They offer the possibility of employing single-cell resolution mapping of the neuronal activity as well as novel techniques for manipulation of in vivo activity, which are currently unavailable in human studies. Here, we review recent developments in the field of rodent empathy research with special emphasis on behavioral paradigms and data on neuronal correlates of emotional contagion. We hope that the use of rodent models will enhance our understanding of social deficits in neuropsychiatric disorders characterized with empathy impairments and the evolutionary continuity of the empathic trait., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The behavioral changes that comprise operant learning are associated with plasticity in early sensory cortices as well as with modulation of gene expression, but the connection between the behavioral, electrophysiological, and molecular changes is only partially understood. We specifically manipulated c-Fos expression, a hallmark of learning-induced synaptic plasticity, in auditory cortex of adult mice using a novel approach based on RNA interference. Locally blocking c-Fos expression caused a specific behavioral deficit in a sound discrimination task, in parallel with decreased cortical experience-dependent plasticity, without affecting baseline excitability or basic auditory processing. Thus, c-Fos-dependent experience-dependent cortical plasticity is necessary for frequency discrimination in an operant behavioral task. Our results connect behavioral, molecular and physiological changes and demonstrate a role of c-Fos in experience-dependent plasticity and learning.

The development of molecular biology methods in the early 1980s led to a better understanding of the role of transcription factors in mammalian cells. The discovery that some transcription factors are critically important for cells to switch between different functional states was fundamental for modern molecular neurobiology. In the 1980s Leszek Kaczmarek proposed that, analogically to the cell cycle or to cell differentiation, long‑term synaptic plasticity, learning, and memory should also require the activity of transcription factors. To test his hypothesis, he focused on c‑Fos. His team showed that the c‑Fos proto‑oncogene is activated by synaptic plasticity and learning, and is required for these phenomena to occur. Subsequent studies showed that timp‑1 and mmp‑9 are c‑Fos effector genes that are required for plasticity. The present review summarizes Kaczmarek's hypothesis and the major evidence that supports it. We\r\nalso describe the ways in which knowledge of the molecular neurobiology of learning and memory advanced because of Kaczmarek's theory. Finally, we briefly discuss the degree to which his hypothesis holds true today after the discovery of non‑coding RNAs, a novel class of regulatory molecules that were not taken into account by Leszek Kaczmarek in the 1980s.

The presence of the hormone oxytocin in the central amygdala makes a mother rat willing to put her life in danger in order to protect her offspring.

Synaptic cell adhesion molecules regulate signal transduction, synaptic function, and plasticity. However, their role in neuronal interactions with the extracellular matrix (ECM) is not well understood. Here we report that the CD44, a transmembrane receptor for hyaluronan, modulates synaptic plasticity. High-resolution ultrastructural analysis showed that CD44 was localized at mature synapses in the adult brain. The reduced expression of CD44 affected the synaptic excitatory transmission of primary hippocampal neurons, simultaneously modifying dendritic spine shape. The frequency of miniature excitatory postsynaptic currents decreased, accompanied by dendritic spine elongation and thinning. These structural and functional alterations went along with a decrease in the number of presynaptic Bassoon puncta, together with a reduction of PSD-95 levels at dendritic spines, suggesting a reduced number of functional synapses. Lack of CD44 also abrogated spine head enlargement upon neuronal stimulation. Moreover, our results indicate that CD44 contributes to proper dendritic spine shape and function by modulating the activity of actin cytoskeleton regulators, that is, Rho GTPases (RhoA, Rac1, and Cdc42). Thus CD44 appears to be a novel molecular player regulating functional and structural plasticity of dendritic spines., (© 2016 Roszkowska et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

Eco-HAB is an open source, RFID-based system for automated measurement and analysis of social preference and in-cohort sociability in mice. The system closely follows murine ethology. It requires no contact between a human experimenter and tested animals, overcoming the confounding factors that lead to irreproducible assessment of murine social behavior between laboratories. In Eco-HAB, group-housed animals live in a spacious, four-compartment apparatus with shadowed areas and narrow tunnels, resembling natural burrows. Eco-HAB allows for assessment of the tendency of mice to voluntarily spend time together in ethologically relevant mouse group sizes. Custom-made software for automated tracking, data extraction, and analysis enables quick evaluation of social impairments. The developed protocols and standardized behavioral measures demonstrate high replicability. Unlike classic three-chambered sociability tests, Eco-HAB provides measurements of spontaneous, ecologically relevant social behaviors in group-housed animals. Results are obtained faster, with less manpower, and without confounding factors., Competing Interests: The authors declare that no competing interests exist.