Serotonergic neuromodulation of synaptic plasticity.

Synaptic plasticity constitutes a fundamental process in the reorganization of neural networks that underlie memory, cognition, emotional responses, and behavioral planning. At the core of this phenomenon lie Hebbian mechanisms, wherein frequent synaptic stimulation induces long-term potentiation (LTP), while less activation leads to long-term depression (LTD). The synaptic reorganization of neuronal networks is regulated by serotonin (5-HT), a neuromodulator capable of modify synaptic plasticity to appropriately respond to mental and behavioral states, such as alertness, attention, concentration, motivation, and mood. Lately, understanding the serotonergic Neuromodulation of synaptic plasticity has become imperative for unraveling its impact on cognitive, emotional, and behavioral functions. Through a comparative analysis across three main forebrain structures-the hippocampus, amygdala, and prefrontal cortex, this review discusses the actions of 5-HT on synaptic plasticity, offering insights into its role as a neuromodulator involved in emotional and cognitive functions. By distinguishing between plastic and metaplastic effects, we provide a comprehensive overview about the mechanisms of 5-HT neuromodulation of synaptic plasticity and associated functions across different brain regions.

Adolescent stress accelerates postpartum novelty recognition impairment in 5xFAD mice.

Pregnancy and the postpartum period induce physiological changes that can influence women's cognitive functions. Alzheimer's disease (AD) has a higher prevalence in women and is exacerbated by early life stress. In the present study, we found that late adolescent social isolation combined with the experience of pregnancy and delivery accelerates the onset of cognitive deficits in 5xFAD dams, particularly affecting their ability to recognize novelty. These cognitive deficits manifested as early as 16 weeks, earlier than the usual timeline for these mice, and were closely associated with increased levels of corticosterone, suggesting dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Notably, the presence of ß-amyloid plaques in brain regions associated with novelty recognition did not significantly contribute to these deficits. This highlights the potential role of stress and HPA axis dysregulation in the development of cognitive impairments related to AD, and underscores the need for further investigation.

Prolonged HPA axis dysregulation in postpartum depression associated with adverse early life experiences: A cross-species translational study.

Childhood and adolescent stress increase the risk of postpartum depression (PPD), often providing an increased probability of treatment refractoriness. Nevertheless, the mechanisms linking childhood/adolescent stress to PPD remain unclear. Our study investigated the longitudinal effects of adolescent stress on the hypothalamic-pituitary-adrenal (HPA) axis and postpartum behaviors in mice and humans. Adolescent social isolation prolonged glucocorticoid elevation, leading to long-lasting postpartum behavioral changes in female mice. These changes were unresponsive to current PPD treatments but improved with post-delivery glucocorticoid receptor antagonist treatment. Childhood/adolescent stress significantly impacted HPA axis dysregulation and PPD in human females. Repurposing glucocorticoid receptor antagonists for some cases of treatment-resistant PPD may be considered.

TREK-1 inhibition promotes synaptic plasticity in the prelimbic cortex.

Synaptic plasticity is one of the putative mechanisms involved in the maturation of the prefrontal cortex (PFC) during postnatal development. Early life stress (ELS) affects the shaping of cortical circuitries through impairment of synaptic plasticity supporting the onset of mood disorders. Growing evidence suggests that dysfunctional postnatal maturation of the prelimbic division (PL) of the PFC might be related to the emergence of depression. The potassium channel TREK-1 has attracted particular interest among many factors that modulate plasticity, concerning synaptic modifications that could underlie mood disorders. Studies have found that ablation of TREK-1 increases the resilience to depression, while rats exposed to ELS exhibit higher TREK-1 levels in the PL. TREK-1 is regulated by multiple intracellular transduction pathways including the ones activated by metabotropic receptors. In the hippocampal neurons, TREK-1 interacts with the serotonergic system, one of the main factors involved in the action of antidepressants. To investigate possible mechanisms related to the antidepressant role of TREK-1, we used brain slice electrophysiology to evaluate the effects of TREK-1 pharmacological blockade on synaptic plasticity at PL circuitry. We extended this investigation to animals subjected to ELS. Our findings suggest that in non-stressed animals, TREK-1 activity is required for the reduction of synaptic responses mediated by the 5HT1A receptor activation. Furthermore, we demonstrate that TREK-1 blockade promotes activity-dependent long-term depression (LTD) when acting in synergy with 5HT1A receptor stimulation. On the other hand, in ELS animals, TREK-1 blockade reduces synaptic transmission and facilitates LTD expression. These results indicate that TREK-1 inhibition stimulates synaptic plasticity in the PL and this effect is more pronounced in animals subjected to ELS during postnatal development.

Promising new pharmacological targets for depression: The search for efficacy.

Pharmacological treatment of major depressive disorder (MDD) still relies on the use of serotonergic drugs, despite their limited efficacy. A few mechanistically new drugs have been developed in recent years, but many fail in clinical trials. Several hypotheses have been proposed to explain MDD pathophysiology, indicating that physiological processes such as neuroplasticity, circadian rhythms, and metabolism are potential targets. Here, we review the current state of pharmacological treatments for MDD, as well as the preclinical and clinical evidence for an antidepressant effect of molecules that target non-serotonergic systems. We offer some insights into the challenges facing the development of new antidepressant drugs, and the prospect of finding more effectiveness for each target discussed.

Adolescent stress impairs postpartum social behavior via anterior insula-prelimbic pathway in mice.

Adolescent stress can be a risk factor for abnormal social behavior in the postpartum period, which critically affects an individual social functioning. Nonetheless, the underlying mechanisms remain unclear. Using a mouse model with optogenetics and in vivo calcium imaging, we found that adolescent psychosocial stress, combined with pregnancy and delivery, caused hypofunction of the glutamatergic pathway from the anterior insula to prelimbic cortex (AI-PrL pathway), which altered PrL neuronal activity, and in turn led to abnormal social behavior. Specifically, the AI-PrL pathway played a crucial role during recognizing the novelty of other mice by modulating "stable neurons" in PrL, which were constantly activated or inhibited by novel mice. We also observed that glucocorticoid receptor signaling in the AI-PrL pathway had a causal role in stress-induced postpartum changes. Our findings provide functional insights into a cortico-cortical pathway underlying adolescent stress-induced postpartum social behavioral deficits.

Adolescent stress impairs postpartum social behavior via anterior insula-prelimbic pathway.

Adolescent stress can be a risk factor for abnormal social behavior in the postpartum period, which critically affects the safety of mothers and children. Nonetheless, the underlying mechanisms remain unclear. Using a newly established mouse model with optogenetics and in vivo calcium imaging, we found that adolescent psychosocial stress, combined with pregnancy and delivery, caused hypofunction of the glutamatergic pathway from the anterior insula to prelimbic cortex (AI-PrL pathway), which altered PrL neuronal activity, and in turn led to abnormal social behavior. Specifically, the AI-PrL pathway played a crucial role during recognizing the novelty of other mice by modulating ″stable neurons″ in PrL, which were constantly activated or inhibited by novel mice. We also observed that glucocorticoid receptor signaling in the AI-PrL pathway had a causal role in stress-induced postpartum changes. Our findings provide novel and functional insights into a cortico-cortical pathway underlying adolescent stress-induced postpartum social behavioral deficits.

Microglial depletion exacerbates motor impairment and dopaminergic neuron loss in a 6-OHDA model of Parkinson's disease.

6-hydroxydopamine (6-OHDA) is a common neurotoxin used to induce Parkinson's disease (PD) in mice, exerting neurotoxic effects through the production of reactive oxygen species and microglial activation. However, the role of microglia in PD is still not clear, with contradictory reports showing neuroprotection or exacerbation of neuronal death. Microglial depletion aggravates motor coordination impairments and reduces tyrosine hydroxylase positive neurons in the substantia nigra pars compacta. Moreover, MeCP2 and Adora1 genes expression were downregulated, suggesting they may be involved in the neurodegenerative process. This study highlights that microglia plays a protective role in dopaminergic neuron survival during the initial phase of PD, and the investigation of the mechanisms of this effect in future studies will help elucidate the pathophysiology of PD.

Serotonergic Modulation of the Excitation/Inhibition Balance in the Visual Cortex.

Serotonergic neurons constitute one of the main systems of neuromodulators, whose diffuse projections regulate the functions of the cerebral cortex. Serotonin (5-HT) is known to play a crucial role in the differential modulation of cortical activity related to behavioral contexts. Some features of the 5-HT signaling organization suggest its possible participation as a modulator of activity-dependent synaptic changes during the critical period of the primary visual cortex (V1). Cells of the serotonergic system are among the first neurons to differentiate and operate. During postnatal development, ramifications from raphe nuclei become massively distributed in the visual cortical area, remarkably increasing the availability of 5-HT for the regulation of excitatory and inhibitory synaptic activity. A substantial amount of evidence has demonstrated that synaptic plasticity at pyramidal neurons of the superficial layers of V1 critically depends on a fine regulation of the balance between excitation and inhibition (E/I). 5-HT could therefore play an important role in controlling this balance, providing the appropriate excitability conditions that favor synaptic modifications. In order to explore this possibility, the present work used in vitro intracellular electrophysiological recording techniques to study the effects of 5-HT on the E/I balance of V1 layer 2/3 neurons, during the critical period. Serotonergic action on the E/I balance has been analyzed on spontaneous activity, evoked synaptic responses, and long-term depression (LTD). Our results pointed out that the predominant action of 5-HT implies a reduction in the E/I balance. 5-HT promoted LTD at excitatory synapses while blocking it at inhibitory synaptic sites, thus shifting the Hebbian alterations of synaptic strength towards lower levels of E/I balance.

5-HT-dependent synaptic plasticity of the prefrontal cortex in postnatal development.

Important functions of the prefrontal cortex (PFC) are established during early life, when neurons exhibit enhanced synaptic plasticity and synaptogenesis. This developmental stage drives the organization of cortical connectivity, responsible for establishing behavioral patterns. Serotonin (5-HT) emerges among the most significant factors that modulate brain activity during postnatal development. In the PFC, activated 5-HT receptors modify neuronal excitability and interact with intracellular signaling involved in synaptic modifications, thus suggesting that 5-HT might participate in early postnatal plasticity. To test this hypothesis, we employed intracellular electrophysiological recordings of PFC layer 5 neurons to study the modulatory effects of 5-HT on plasticity induced by theta-burst stimulation (TBS) in two postnatal periods of rats. Our results indicate that 5-HT is essential for TBS to result in synaptic changes during the third postnatal week, but not later. TBS coupled with 5-HT2A or 5-HT1A and 5-HT7 receptors stimulation leads to long-term depression (LTD). On the other hand, TBS and synergic activation of 5-HT1A, 5-HT2A, and 5-HT7 receptors lead to long-term potentiation (LTP). Finally, we also show that 5-HT dependent synaptic plasticity of the PFC is impaired in animals that are exposed to early-life chronic stress.

Are the Anterior and Mid-Cingulate Cortices Distinct in Rodents?

The prefrontal cortex (PFC) is involved in cognitive control, emotional regulation, and motivation. In this Perspective article, we discuss the nomenclature of the subdivisions of the medial prefrontal cortex (mPFC), since the anatomical definitions of the PFC subregions have been confusing. Although the mid-cingulate cortex (MCC) and anterior cingulate cortex (ACC) have distinct features in humans and non-human primates, it is unclear whether these regions serve different functions in rodents. Accurate mapping of the cingulate cortex in rodents is important to allow comparisons between species. A proposed change in the nomenclature of the rodent cingulate cortex to anterior cingulate cortex (aCg) and mid-cingulate cortex (mCg) is presented based on our data. We show evidence for distinct cortico-cortical projections from the aCg and mCg to the PrL. The aCg→PrL neurons were abundant in layer VI, while the mCg→PrL neurons were mainly distributed in layer V. In addition, a sex difference was detected in the aCg, with males having a higher proportion of layer V neurons projecting to the PrL than females. Based on this laminar distribution and considering that layer V and VI send efferent projections to different brain areas such as the brain stem, amygdala, and thalamus, we propose that aCg and mCg need to be considered separate entities for future rodent studies. This new definition will put into perspective the role of rodent cingulate cortex in diverse aspects of cognition and facilitate interspecies comparisons in cingulate cortex research.

Maternal separation impairs mother's cognition 1 month beyond the separation.

OBJECTIVE: Separation of pups from their dam during the infancy not only has detrimental effects on the pups' brain but also affects dams' behavior. Postpartum stress may affect mothers' cognitive functions. In the present study, by using a 180-min day-1 maternal separation (MS) paradigm, we assessed anxiety-like behavior and locomotor activity of rat dams which experienced separation from postnatal day (PND) 1 until weaning. We tried for the first time to clarify whether such separation impairs dam's performance in the Morris water maze. METHOD: We assessed dams' behavior at three time points: 24 h, 1 week, and 1 month after weaning. Therefore, the six groups consisted of control (CTRL) 24 h, 1 week, and 1 month and MS 24 h, 1 week, and 1 month, which was allocated in this study. RESULTS: Our results revealed that although MS-24 h and MS-1 week groups had intact locomotor activity, MS-1 month group showed less locomotor activity in the open field. Moreover, MS-induced anxiety-like behavior was more pronounced in MS-1 week and MS-1 month dams. Spatial learning and memory was also impaired only in MS-1 month dams. CONCLUSION: We can conclude that MS induces cognitive impairments in dam that may appear not immediately after the separation but a few weeks after such stressful event.

Metaplasticity in the Visual Cortex: Crosstalk Between Visual Experience and Reactive Oxygen Species.

Metaplasticity is the regulation of synaptic plasticity based on the history of previous synaptic activation. This concept was formulated after observing that synaptic changes in the visual cortex are not fixed, but dynamic and dependent on the history of visual information flux. In visual cortical neurons, sustained synaptic stimulation activate the enzymatic complex NOX2, resulting in the generation of reactive oxygen species (ROS). NOX2 is the main molecular structure responsible for translating neural activity into redox modulation of intracellular signaling pathways involved in plastic changes. Here, we studied the interaction between NOX2 and visual experience as metaplastic factors regulating synaptic plasticity at the supergranular layers of the mouse visual cortex. We found that genetic inhibition of NOX2 reverses the polarizing effects of dark rearing from LTP to LTD. In addition, we demonstrate that this process relies on changes in the NMDA receptor functioning. Altogether, this work indicates a role of ROS in the activity-dependent regulation of cortical synaptic plasticity.SIGNIFICANCE STATEMENT Synaptic plasticity in the visual cortex is modulated by the history of sensory experience and this modulation has been defined as metaplasticity. Dark rearing facilitates synaptic potentiation as a mechanism optimizing the range of synaptic modification. This process requires the production of reactive oxygen species mediated by the enzymatic complex NOX2. If the activity of NOX2 is inhibited, then visual deprivation results in synaptic depression. These findings increase our knowledge about metaplasticity and help in our understanding of how neural activity modulates cellular mechanisms of synaptic change.

Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity.

In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated.

Acute stress affects the global DNA methylation profile in rat brain: modulation by physical exercise.

The vulnerability of epigenetic marks of brain cells to environmental stimuli and its implication for health have been recently debated. Thus, we used the rat model of acute restraint stress (ARS) to evaluate the impact of stress on the global DNA methylation and on the expression of the Dnmt1 and Bdnf genes of hippocampus, cortex, hypothalamus and periaqueductal gray (PAG). Furthermore, we verified the potential of physical exercise to modulate epigenetic responses evoked by ARS. Sedentary male Wistar rats were submitted to ARS at the 75th postnatal day (PND), whereas animals from a physically active group were previously submitted to swimming sessions (35-74th PND) and to ARS at the 75th PND. Global DNA methylation profile was quantified using an ELISA-based method and the quantitative expression of the Dnmt1 and Bdnf genes was evaluated by real-time PCR. ARS induced a decrease in global DNA methylation in hippocampus, cortex and PAG of sedentary animals and an increased expression of Bdnf in PAG. No change in DNA methylation was associated with ARS in the exercised animals, although it was associated with abnormal expression of Dnmt1 and Bdnf in cortex, hypothalamus and PAG. Our data reveal that ARS evokes adaptive changes in global DNA methylation of rat brain that are independent of the expression of the Dnmt1 gene but might be linked to abnormal expression of the Bdnf gene in the PAG. Furthermore, our evidence indicates that physical exercise has the potential to modulate changes in DNA methylation and gene expression consequent to ARS.

Fluoxetine exposure during pregnancy and lactation: Effects on acute stress response and behavior in the novelty-suppressed feeding are age and gender-dependent in rats.

Fluoxetine (FLX) is commonly used to treat anxiety and depressive disorders in pregnant women. Since FLX crosses the placenta and is excreted in milk, maternal treatment with this antidepressant may expose the fetus and neonate to increased levels of serotonin (5-HT). Long-term behavioral abnormalities have been reported in rodents exposed to higher levels of 5-HT during neurodevelopment. In this study we evaluated if maternal exposure to FLX during pregnancy and lactation would result in behavioral and/or stress response disruption in adolescent and adult rats. Our results indicate that exposure to FLX influenced restraint stress-induced Fos expression in the amygdala in a gender and age-specific manner. In male animals, a decreased expression was observed in the basolateral amygdala at adolescence and adulthood; whereas at adulthood, a decrease was also observed in the medial amygdala. A lack of FLX exposure effect was observed in females and also in the paraventricular nucleus of both genders. Regarding the behavioral evaluation, FLX exposure did not induce anhedonia in the sucrose preference test but decreased the latency to feed of both male and female adolescent rats evaluated in the novelty-suppressed feeding test. In conclusion, FLX exposure during pregnancy and lactation decreases acute amygdalar stress response to a psychological stressor in males (adolescents and adults) as well as influences the behavior of adolescents (males and females) in a model that evaluates anxiety and/or depressive-like behavior. Even though FLX seems to be a developmental neurotoxicant, the translation of these findings to human safe assessment remains to be determined since it is recognized that not treating a pregnant or lactating woman may also impact negatively the development of the descendants.