Physiological and behavioral contagion/buffering effects of chronic unpredictable stress in a socially enriched environment: A preliminary study.

Rodents are sensitive to the emotional state of conspecifics. While the presence of affiliative social partners mitigates the physiological response to stressors (buffering), the partners of stressed individuals show behavioral and endocrine changes indicating that stress parameters can be transmitted across the group members (contagion). In this study, we investigated the social contagion/buffering phenomena in behavior and neuroendocrine mechanisms after exposure to chronic stress, in groups of rats living in the PhenoWorld (PhW). Three groups were tested (8 stressed rats, 8 unstressed rats, and a mixed group with 4 and 4) and these were analyzed under 4 conditions: stressed (pure stress group, n = 8), unstressed (naive control group, n = 8), stressed from mixed group (stressed companion group, n = 8), unstressed from mixed group (unstressed companion group, n = 8. While naive control animals remained undisturbed, pure stress group animals were all exposed to stress. Half of the animals under the mixed-treatment condition were exposed to stress (stressed companion group) and cohabitated with their unstressed partners (unstressed companion group). We confirmed the well-established chronic unpredictable stress (CUS) effects in physiological, behavioral, and neuroendocrine endpoints; body weight gain, open arm entries and time in EPM, and oxytocin receptor expression levels in the amygdala decreased by stress exposure, whereas adrenal weight was increased by stress. Furthermore, we found that playing, rearing and solitary resting behaviors decreased, whereas huddling behavior increased by CUS. In addition, we detected significant increases (stress-buffering) in body weight gain and huddling behaviors between pure stress and stress companion animals, and significant stress contagion effects in emotional behavior and oxytocin receptor expression levels between naive control and control companion groups. Hence, we demonstrate buffering and contagion effects were evident in physiological parameters, emotional behaviors, and social home-cage behaviors of rats and we suggest a possible mediation of these effects by oxytocin neurotransmission. In conclusion, the results herein suggest that the stress status of animals living in the same housing environment influences the behavior of the group.

Nucleus accumbens neurons dynamically respond to appetitive and aversive associative learning.

To survive, individuals must learn to associate cues in the environment with emotionally relevant outcomes. This association is partially mediated by the nucleus accumbens (NAc), a key brain region of the reward circuit that is mainly composed by GABAergic medium spiny neurons (MSNs), that express either dopamine receptor D1 or D2. Recent studies showed that both populations can drive reward and aversion, however, the activity of these neurons during appetitive and aversive Pavlovian conditioning remains to be determined. Here, we investigated the relevance of D1- and D2-neurons in associative learning, by measuring calcium transients with fiber photometry during appetitive and aversive Pavlovian tasks in mice. Sucrose was used as a positive valence unconditioned stimulus (US) and foot shock was used as a negative valence US. We show that during appetitive Pavlovian conditioning, D1- and D2-neurons exhibit a general increase in activity in response to the conditioned stimuli (CS). Interestingly, D1- and D2-neurons present distinct changes in activity after sucrose consumption that dynamically evolve throughout learning. During the aversive Pavlovian conditioning, D1- and D2-neurons present an increase in the activity in response to the CS and to the US (shock). Our data support a model in which D1- and D2-neurons are concurrently activated during appetitive and aversive conditioning.

Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Treating Parkinson's Disease with Human Bone Marrow Mesenchymal Stem Cell Secretome: A Translational Investigation Using Human Brain Organoids and Different Routes of In Vivo Administration.

Parkinson's disease (PD) is the most common movement disorder, characterized by the progressive loss of dopaminergic neurons from the nigrostriatal system. Currently, there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Mesenchymal stem cells (MSCs) are one of the most extensively studied cell sources for regenerative medicine applications, particularly due to the release of soluble factors and vesicles, known as secretome. The main goal of this work was to address the therapeutic potential of the secretome collected from bone-marrow-derived MSCs (BM-MSCs) using different models of the disease. Firstly, we took advantage of an optimized human midbrain-specific organoid system to model PD in vitro using a neurotoxin-induced model through 6-hydroxydopamine (6-OHDA) exposure. In vivo, we evaluated the effects of BM-MSC secretome comparing two different routes of secretome administration: intracerebral injections (a two-site single administration) against multiple systemic administration. The secretome of BM-MSCs was able to protect from dopaminergic neuronal loss, these effects being more evident in vivo. The BM-MSC secretome led to motor function recovery and dopaminergic loss protection; however, multiple systemic administrations resulted in larger therapeutic effects, making this result extremely relevant for potential future clinical applications.

A novel perspective on the role of nucleus accumbens neurons in encoding associative learning.

The nucleus accumbens (NAc) has been considered a key brain region for encoding reward/aversion and cue-outcome associations. These processes are encoded by medium spiny neurons that express either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). Despite the well-established role of NAc neurons in encoding reward/aversion, the underlying processing by D1-/D2-MSNs remains largely unknown. Recent electrophysiological, optogenetic and calcium imaging studies provided insight on the complex role of D1- and D2-MSNs in these behaviours and helped to clarify their involvement in associative learning. Here, we critically discuss findings supporting an intricate and complementary role of NAc D1- and D2-MSNs in associative learning, emphasizing the need for additional studies in order to fully understand the role of these neurons in behaviour.

Involvement of nucleus accumbens D2-medium spiny neurons projecting to the ventral pallidum in anxiety-like behaviour.

BACKGROUND: The nucleus accumbens (NAcc) is a crucial brain region for emotionally relevant behaviours. The NAcc is mainly composed of medium spiny neurons (MSNs) expressing either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). The D1-MSNs project to the ventral tegmental area (VTA) and the ventral pallidum (VP), whereas the D2-MSNs project only to the VP. The D1- and D2-MSNs have been associated with depression-like behaviours, but their contribution to anxiety remains to be determined. METHODS: We used optogenetic tools to selectively manipulate D1-MSN projections from the NAcc core to the VP or VTA and D2-MSN projections to the VP during validated anxiety-producing behavioural procedures in naive mice. In addition, we assessed the effects of optical stimulation on neuronal activity using in vivo electrophysiologic recordings in anesthetized animals. RESULTS: Optogenetic activation of D1-MSN projections to the VTA or VP did not trigger anxiety-like behaviour. However, optical activation of D2-MSN projections to the VP significantly increased anxiety-like behaviour. This phenotype was associated with a decrease in the neuronal activity of putative GABAergic neurons in the VP. Importantly, pretreating D2-MSN-VP animals with the γ-aminobutyric acid modulator diazepam prevented the optically triggered anxiety-like behaviour. LIMITATIONS: The exclusive use of males in the behavioural tests limits broader interpretation of the findings. Although we used optogenetic conditions that trigger quasi-physiologic changes, there are caveats associated with the artificial manipulation of neuronal activity. CONCLUSION: The D2-MSN-VP projections contributed to the development of anxiety-like behaviour, through modulation of GABAergic activity in the VP.

Home-cage behavior is impacted by stress exposure in rats.

Being social animals, rats exhibit a range of social behaviors that help them build social bonds and maintain group cohesion. Behavior is influenced by multiple factors, including stress exposure, and the expression of the impact of stress on both social and non-social behaviors may also be affected by the living conditions of rats. In this study, we explored the physiological and behavioral effects of chronic unpredictable stress on group-housed rats in the PhenoWorld (PhW), a socially and physically enriched environment closer to real-life conditions. Two independent experiments were performed: one in the control condition (PhW control, n = 8) and one in the stress condition (PhW stress, n = 8). Control animals remained undisturbed except for cage cleaning and daily handling procedures. Stress group animals were all exposed to chronic unpredictable stress. Data confirm that stress exposure triggers anxiety-like behavior in the PhW. In terms of home-cage behaviors, we found that stress affects social behaviors (by decreased playing and increased huddling behaviors) and non-social behaviors (as shown by the decrease in rearing and walking behaviors). These results are of relevance to expand our knowledge on the influence of stress on social and non-social behaviors, which are of importance to understand better species-typical behaviors.

Ventral pallidal regulation of motivated behaviors and reinforcement.

The interconnected nuclei of the ventral basal ganglia have long been identified as key regulators of motivated behavior, and dysfunction of this circuit is strongly implicated in mood and substance use disorders. The ventral pallidum (VP) is a central node of the ventral basal ganglia, and recent studies have revealed complex VP cellular heterogeneity and cell- and circuit-specific regulation of reward, aversion, motivation, and drug-seeking behaviors. Although the VP is canonically considered a relay and output structure for this circuit, emerging data indicate that the VP is a central hub in an extensive network for reward processing and the regulation of motivation that extends beyond classically defined basal ganglia borders. VP neurons respond temporally faster and show more advanced reward coding and prediction error processing than neurons in the upstream nucleus accumbens, and regulate the activity of the ventral mesencephalon dopamine system. This review will summarize recent findings in the literature and provide an update on the complex cellular heterogeneity and cell- and circuit-specific regulation of motivated behaviors and reinforcement by the VP with a specific focus on mood and substance use disorders. In addition, we will discuss mechanisms by which stress and drug exposure alter the functioning of the VP and produce susceptibility to neuropsychiatric disorders. Lastly, we will outline unanswered questions and identify future directions for studies necessary to further clarify the central role of VP neurons in the regulation of motivated behaviors. Significance: Research in the last decade has revealed a complex cell- and circuit-specific role for the VP in reward processing and the regulation of motivated behaviors. Novel insights obtained using cell- and circuit-specific interrogation strategies have led to a major shift in our understanding of this region. Here, we provide a comprehensive review of the VP in which we integrate novel findings with the existing literature and highlight the emerging role of the VP as a linchpin of the neural systems that regulate motivation, reward, and aversion. In addition, we discuss the dysfunction of the VP in animal models of neuropsychiatric disorders.

A novel isolation method for spontaneously released extracellular vesicles from brain tissue and its implications for stress-driven brain pathology.

BACKGROUND: Extracellular vesicles (EVs), including small EVs (sEVs) such as exosomes, exhibit great potential for the diagnosis and treatment of brain disorders, representing a valuable tool for precision medicine. The latter demands high-quality human biospecimens, especially in complex disorders in which pathological and specimen heterogeneity, as well as diverse individual clinical profile, often complicate the development of precision therapeutic schemes and patient-tailored treatments. Thus, the collection and characterization of physiologically relevant sEVs are of the utmost importance. However, standard brain EV isolation approaches rely on tissue dissociation, which can contaminate EV fractions with intracellular vesicles. METHODS: Based on multiscale analytical platforms such as cryo-EM, label-free proteomics, advanced flow cytometry, and ExoView analyses, we compared and characterized the EV fraction isolated with this novel method with a classical digestion-based EV isolation procedure. Moreover, EV biogenesis was pharmacologically manipulated with either GW4869 or picrotoxin to assess the validity of the spontaneous-release method, while the injection of labelled-EVs into the mouse brain further supported the integrity of the isolated vesicles. RESULTS: We hereby present an efficient purification method that captures a sEV-enriched population spontaneously released by mouse and human brain tissue. In addition, we tested the significance of the release method under conditions where biogenesis/secretion of sEVs was pharmacologically manipulated, as well as under animals' exposure to chronic stress, a clinically relevant precipitant of brain pathologies, such as depression and Alzheimer's disease. Our findings show that the released method monitors the drug-evoked inhibition or enhancement of sEVs secretion while chronic stress induces the secretion of brain exosomes accompanied by memory loss and mood deficits suggesting a potential role of sEVs in the brain response to stress and related stress-driven brain pathology. CONCLUSIONS: Overall, the spontaneous release method of sEV yield may contribute to the characterization and biomarker profile of physiologically relevant brain-derived sEVs in brain function and pathology. Video Abstract.

Prenatal dexamethasone exposure alters effort decision making and triggers nucleus accumbens and anterior cingulate cortex functional changes in male rats.

Daily, individuals select actions based on cost-benefit to allocate resources into goal-directed actions. Different brain regions coordinate this complex decision, including the nucleus accumbens (NAc), anterior cingulate cortex (ACC), and ventral tegmental area (VTA). In utero exposure to synthetic glucocorticoids (iuGC), such as dexamethasone, triggers prominent motivation deficits but the impact of this exposure in the ACC-NAc and/or ACC-VTA circuits is unknown. Here, we show that iuGC exposure causes decreased motivation for natural rewards (food) and impaired effort-based decision-making. Importantly, reduced neuronal activation (number of c-fos+ neurons) was observed in the NAc core and ACC of iuGC rats in comparison to CTR rats after performing the effort-based decision-making task. In addition, iuGC treatment led to increased NAc and ACC basal neuronal activity. Electrophysiological recordings during optogenetic modulation of ACC terminals in the NAc revealed that the ACC-NAc circuit is dysfunctional in iuGC animals. These data suggest that iuGC animals present motivational and effort-based decision-making deficits that can be associated with the observed ACC-NAc dysfunction.

The Duration of Stress Determines Sex Specificities in the Vulnerability to Depression and in the Morphologic Remodeling of Neurons and Microglia.

Stress exposure has been shown to induce a variety of molecular and functional alterations associated with anxiety and depression. Some studies suggest that microglia, the immune cells of the brain, play a significant role in determining neuronal and behavioral responses to chronic stress and also contribute to the development of stress-related psychopathologies. However, little is known about the impact of the duration of stress exposure upon microglia and neurons morphology, particularly considering sex differences. This issue deserves particular investigation, considering that the process of morphologic remodeling of neurons and microglia is usually accompanied by functional changes with behavioral expression. Here, we examine the effects of short and long unpredictable chronic mild stress (uCMS) protocols on behavior, evaluating in parallel microglia and neurons morphology in the dorsal hippocampus (dHIP) and in the nucleus accumbens (NAc), two brain regions involved in the etiology of depression. We report that long-term uCMS induced more behavioral alterations in males, which present anxiety and depression-like phenotypes (anhedonia and helplessness behavior), while females only display anxiety-like behavior. After short-term uCMS, both sexes presented anxiety-like behavior. Microglia cells undergo a process of morphologic adaptation to short-term uCMS, dependent on sex, in the NAc: we observed a hypertrophy in males and an atrophy in females, transient effects that do not persist after long-term uCMS. In the dHIP, the morphologic adaptation of microglia is only observed in females (hypertrophy) and after the protocol of long uCMS. Interestingly, males are more vulnerable to neuronal morphological alterations in a region-specific manner: dendritic atrophy in granule neurons of the dHIP and hypertrophy in the medium spiny neurons of the NAc, both after short- or long-term uCMS. The morphology of neurons in these brain regions were not affected in females. These findings raise the possibility that, by differentially affecting neurons and microglia in dHIP and NAc, chronic stress may contribute for differences in the clinical presentation of stress-related disorders under the control of sex-specific mechanisms.

Distinct role of nucleus accumbens D2-MSN projections to ventral pallidum in different phases of motivated behavior.

The nucleus accumbens (NAc) is a key region in motivated behaviors. NAc medium spiny neurons (MSNs) are divided into those expressing dopamine receptor D1 or D2. Classically, D1- and D2-MSNs have been described as having opposing roles in reinforcement, but recent evidence suggests a more complex role for D2-MSNs. Here, we show that optogenetic modulation of D2-MSN to ventral pallidum (VP) projections during different stages of motivated behavior has contrasting effects in motivation. Activation of D2-MSN-VP projections during a reward-predicting cue results in increased motivational drive, whereas activation at reward delivery decreases motivation; optical inhibition triggers the opposite behavioral effect. In addition, in a free-choice instrumental task, animals prefer the lever that originates one pellet in opposition to pellet plus D2-MSN-VP optogenetic activation and vice versa for optogenetic inhibition. In summary, D2-MSN-VP projections play different, and even opposing, roles in distinct phases of motivated behavior.

Preclinical Assessment of Mesenchymal-Stem-Cell-Based Therapies in Spinocerebellar Ataxia Type 3.

The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies for neurodegenerative diseases, including spinocerebellar ataxias. Spinocerebellar ataxia type 3 (SCA3)-or Machado-Joseph disease (MJD)-is the most common dominant ataxia, being mainly characterized by motor deficits; however, SCA3/MJD has a complex and heterogeneous pathophysiology, involving many CNS brain regions, contributing to the lack of effective therapies. Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for CNS disorders. Beyond their differentiation potential, MSCs secrete a broad range of neuroregulatory factors that can promote relevant neuroprotective and immunomodulatory actions in different pathophysiological contexts. The objective of this work was to study the effects of (1) human MSC transplantation and (2) human MSC secretome (CM) administration on disease progression in vivo, using the CMVMJD135 mouse model of SCA3/MJD. Our results showed that a single CM administration was more beneficial than MSC transplantation-particularly in the cerebellum and basal ganglia-while no motor improvement was observed when these cell-based therapeutic approaches were applied in the spinal cord. However, the effects observed were mild and transient, suggesting that continuous or repeated administration would be needed, which should be further tested.

Constitutive deficiency of the neurogenic hippocampal modulator AP2γ promotes anxiety-like behavior and cumulative memory deficits in mice from juvenile to adult periods.

The transcription factor activating protein two gamma (AP2γ) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive and heterozygous AP2γ deletion in mice from early postnatal development until adulthood. AP2γ deficiency promotes downregulation of hippocampal glutamatergic neurogenesis, altering the ontogeny of emotional and memory behaviors associated with hippocampus formation. The impairments induced by AP2γ constitutive deletion since early development leads to an anxious-like phenotype and memory impairments as early as the juvenile phase. These behavioral impairments either persist from the juvenile phase to adulthood or emerge in adult mice with deficits in behavioral flexibility and object location recognition. Collectively, we observed a progressive and cumulative impact of constitutive AP2γ deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with functional behavioral impairments. The results herein presented demonstrate the modulatory role exerted by the AP2γ transcription factor and the relevance of hippocampal neurogenesis in the development of emotional states and memory processes.

Unilateral Intrastriatal 6-Hydroxydopamine Lesion in Mice: A Closer Look into Non-Motor Phenotype and Glial Response.

Parkinson's disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson's disease (PD) in rodents. Despite commonly used in rats, it can be challenging to reproduce a similar lesion in mice. Moreover, there is a lack of characterization of the extent of behavioral deficits and of the neuronal loss/neurotransmitter system in unilateral lesion mouse models. In this study, we present an extensive behavioral and histological characterization of a unilateral intrastriatal 6-OHDA mouse model. Our results indicate significant alterations in balance and fine motor coordination, voluntary locomotion, and in the asymmetry's degree of forelimb use in 6-OHDA lesioned animals, accompanied by a decrease in self-care and motivational behavior, common features of depressive-like symptomatology. These results were accompanied by a decrease in tyrosine hydroxylase (TH)-labelling and dopamine levels within the nigrostriatal pathway. Additionally, we also identify a marked astrocytic reaction, as well as proliferative and reactive microglia in lesioned areas. These results confirm the use of unilateral intrastriatal 6-OHDA mice for the generation of a mild model of nigrostriatal degeneration and further evidences the recapitulation of key aspects of PD, thereby being suitable for future studies beholding new therapeutical interventions for this disease.

Laterodorsal tegmentum-ventral tegmental area projections encode positive reinforcement signals.

The laterodorsal tegmentum (LDT) is a brainstem nucleus classically involved in REM sleep and attention, and that has recently been associated with reward-related behaviors, as it controls the activity of ventral tegmental area (VTA) dopaminergic neurons, modulating dopamine release in the nucleus accumbens. To further understand the role of LDT-VTA inputs in reinforcement, we optogenetically manipulated these inputs during different behavioral paradigms in male rats. We found that in a two-choice instrumental task, optical activation of LDT-VTA projections shifts and amplifies preference to the laser-paired reward in comparison to an otherwise equal reward; the opposite was observed with inhibition experiments. In a progressive ratio task, LDT-VTA activation boosts motivation, that is, enhances the willingness to work to get the reward associated with LDT-VTA stimulation; and the reverse occurs when inhibiting these inputs. Animals abolished preference if the reward was omitted, suggesting that LDT-VTA stimulation adds/decreases value to the stimulation-paired reward. In addition, we show that LDT-VTA optical activation induces robust preference in the conditioned and real-time place preference tests, while optical inhibition induces aversion. The behavioral findings are supported by electrophysiological recordings and c-fos immunofluorescence correlates in downstream target regions. In LDT-VTA ChR2 animals, we observed an increase in the recruitment of lateral VTA dopamine neurons and D1 neurons from nucleus accumbens core and shell; whereas in LDT-VTA NpHR animals, D2 neurons appear to be preferentially recruited. Collectively, these data show that the LDT-VTA inputs encode positive reinforcement signals and are important for different dimensions of reward-related behaviors.

Resilience to stress and sex-specific remodeling of microglia and neuronal morphology in a rat model of anxiety and anhedonia.

Prenatal exposure to stress or glucocorticoids (GC) is associated with the appearance of psychiatric diseases later in life. Microglia, the immune cells of the brain, are altered in stress-related disorders. Synthetic GC such as dexamethasone (DEX) are commonly prescribed in case of preterm risk labour in order to promote fetal lung maturation. Recently, we reported long-lasting differences in microglia morphology in a model of in utero exposure to DEX (iuDEX), that presents an anxious phenotype. However, it is still unclear if stress differentially affects iuDEX males and females. In this work, we evaluated how iuDEX animals of both sexes cope with chronic mild stress for 2 weeks. We evaluated emotional behavior and microglia and neuronal morphology in the dorsal hippocampus (dHIP) and nucleus accumbens (NAc), two brain regions involved in emotion-related disorders. We report that males and females prenatally exposed to DEX have better performance in anxiety- and depression-related behavioral tests after chronic stress exposure in adulthood than non-exposed animals. Interestingly, iuDEX animals present sex-dependent changes in microglia morphology in the dHIP (hypertrophy in females) and in the NAc (atrophy in females and hypertrophy in males). After chronic stress, these cells undergo sex-specific morphological remodeling. Paralleled to these alterations in cytoarchitecture of microglia, we report inter-regional differences in dendritic morphology in a sex-specific manner. iuDEX females present fewer complex neurons in the NAc, whereas iuDEX males presented less complex neuronal morphology in the dHIP. Interestingly, these alterations were modified by stress exposure. Our work shows that stressful events during pregnancy can exert a preserved sex-specific effect in adulthood. Although the role of the observed cellular remodeling is still unknown, sex-specific differences in microglia plasticity induced by long-term stress exposure may anticipate differences in drug efficacy in the context of stress-induced anxiety- or depression-related behaviors.

Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aß-evoked hippocampal pathology.

Despite considerable progress in the understanding of its neuropathology, Alzheimer's disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aß) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound. Using non-transgenic animal model of Aß oligomer injection as well as the combined stress and Aß i.c.v. infusion, we demonstrate that positive allosteric modulation of AMPA receptors by PAM-AMPA treatment reverted memory, but not mood, deficits. Furthermore, PAM-AMPA treatment reverted stress/Aß-driven synaptic missorting of Tau and associated Fyn/GluN2B-driven excitotoxic synaptic signaling accompanied by recovery of neurotransmitter levels in the hippocampus. Our findings suggest that positive allosteric modulation of AMPA receptors restores synaptic integrity and cognitive performance in stress- and Aß-evoked hippocampal pathology. As the prevalence of AD is increasing at an alarming rate, novel therapeutic targeting of glutamatergic signaling should be further explored against the early stages of AD synaptic malfunction with the goal of attenuating further synaptic damage before it becomes irreversible.

Splenic sympathetic signaling contributes to acute neutrophil infiltration of the injured spinal cord.

BACKGROUND: Alterations in the immune system are a complication of spinal cord injury (SCI) and have been linked to an excessive sympathetic outflow to lymphoid organs. Still unknown is whether these peripheral immune changes also contribute for the deleterious inflammatory response mounted at the injured spinal cord. METHODS: We analyzed different molecular outputs of the splenic sympathetic signaling for the first 24 h after a thoracic compression SCI. We also analyzed the effect of ablating the splenic sympathetic signaling to the innate immune and inflammatory response at the spleen and spinal cord 24 h after injury. RESULTS: We found that norepinephrine (NE) levels were already raised at this time-point. Low doses of NE stimulation of splenocytes in vitro mainly affected the neutrophils' population promoting an increase in both frequency and numbers. Interestingly, the interruption of the sympathetic communication to the spleen, by ablating the splenic nerve, resulted in reduced frequencies and numbers of neutrophils both at the spleen and spinal cord 1 day post-injury. CONCLUSION: Collectively, our data demonstrates that the splenic sympathetic signaling is involved in the infiltration of neutrophils after spinal cord injury. Our findings give new mechanistic insights into the dysfunctional regulation of the inflammatory response mounted at the injured spinal cord.

Signatures of brain criticality unveiled by maximum entropy analysis across cortical states.

It has recently been reported that statistical signatures of brain criticality, obtained from distributions of neuronal avalanches, can depend on the cortical state. We revisit these claims with a completely different and independent approach, employing a maximum entropy model to test whether signatures of criticality appear in urethane-anesthetized rats. To account for the spontaneous variation of cortical states, we parse the time series and perform the maximum entropy analysis as a function of the variability of the population spiking activity. To compare data sets with different numbers of neurons, we define a normalized distance to criticality that takes into account the peak and width of the specific heat curve. We found a universal collapse of the normalized distance to criticality dependence on the cortical state, on an animal by animal basis. This indicates a universal dynamics and a critical point at an intermediate value of spiking variability.