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Background Brain-resident microglia have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacological depletion of microglia during whole-brain radiotherapy prevents synaptic loss and long-term recognition memory deficits. However, the origin or repopulated cells and the mechanisms behind these protective effects are unknown. Methods CD45low/int/CD11b+ cells from naïve brains, irradiated brains, PLX5622-treated brains and PLX5622 + whole-brain radiotherapy-treated brains were FACS sorted and sequenced for transcriptomic comparisons. Bone marrow chimeras were used to trace the origin and long-term morphology of repopulated cells after PLX5622 and whole-brain radiotherapy. FACS analyses of intrinsic and exotic synaptic compartments were used to measure phagocytic activities of microglia and repopulated cells. In addition, concussive brain injuries were given to PLX5622 and brain-irradiated mice to study the potential protective functions of repopulated cells after PLX5622 + whole-brain radiotherapy. Results After a combination of whole-brain radiotherapy and microglia depletion, repopulated cells are brain-engrafted macrophages that originate from circulating monocytes. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. In addition, brain-engrafted macrophages display reduced phagocytic activity for synaptic compartments compared to microglia from normal brains in response to a secondary concussive brain injury. Importantly, replacement of microglia by brain-engrafted macrophages spare mice from whole-brain radiotherapy-induced long-term cognitive deficits, and prevent concussive injury-induced memory loss. Conclusions Brain-engrafted macrophages prevent radiation- and concussion-induced brain injuries and cognitive deficits.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a >2-fold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, axsnd inhibition of the ISR — even weeks after injury — can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed the structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach for the clinical treatment of chronic cognitive deficits after TBI.Significance StatementAfter traumatic brain injury, temporary pharmacological inhibition of the integrated stress response (ISR), with a small-molecule inhibitor (ISRIB), rescued long lasting trauma-induced cognitive deficits. Here, we found that ISRIB treatment rapidly and persistently reversed the aberrant changes in cortical spine dynamics in the parietal cortex while rescuing working memory deficits. These data suggests that the link between the ISR and memory function involves, at least in part, changes in neuronal structure. Targeting ISR activation could serve as a promising approach for the clinical treatment of chronic cognitive deficits after brain injuries.

Neuroinflammation has emerged as an important factor in the molecular underpinnings of major depressive disorder (MDD) pathophysiology and in the mechanism of action of antidepressants. Among the inflammatory mediators dysregulated in depressed patients, interleukin (IL)-6 has recently been proposed to play a crucial role. IL-6 activates a signaling pathway comprising the JAK/STAT proteins and characterized by a specific negative feedback loop exerted by the cytoplasmic protein suppressor of cytokine signalling-3 (SOCS3). On these bases, here, we explored the potential involvement of IL-6 signaling in the ability of the antidepressant drug agomelatine to normalize the anhedonic-like phenotype induced in the rat by chronic stress exposure. To this aim, adult male Wistar rats were subjected to the chronic mild stress (CMS) paradigm and chronically treated with vehicle or agomelatine. The behavioral evaluation was assessed by the sucrose consumption test, whereas molecular analyses were performed in the prefrontal cortex. We found that CMS was able to stimulate IL-6 production and signaling, including SOCS3 gene and protein expression, but the SOCS3-mediated feedback-loop inhibition failed to suppress the IL-6 cascade in stressed animals. Conversely, agomelatine treatment normalized the stress-induced decrease in sucrose consumption and restored the negative modulation of the IL-6 signaling via SOCS3 expression and activity. Our results provide additional information about the pleiotropic mechanisms that contribute to agomelatine's therapeutic effects.

Rationale Although the occurrence of stressful events is very common during life, their impact may be different depending on the experience severity and duration. Specifically, acute challenges may trigger adaptive responses and even improve the individual’s performance. However, such a physiological positive coping can only take place if the underlying molecular mechanisms are properly functioning. Indeed, if these systems are compromised by genetic factors or previous adverse conditions, the response set in motion by an acute challenge may be maladaptive and even cause the insurgence or the relapse of stress-related psychiatric disorders. Objectives On these bases, we evaluated in the rat brain the role of the antioxidant component of the redox machinery on the acute stress responsiveness and its modulation by potential detrimental or beneficial events. Methods The expression of several antioxidant enzymes was assessed in different brain areas of adult male rats exposed to acute stress 3 weeks after a chronic immobilization paradigm with or without a concomitant treatment with the antipsychotic lurasidone. Results The acute challenge was able to trigger a marked antioxidant response that, despite the washout period, was impaired by the previous adverse experience and restored by lurasidone in an anatomical-specific manner. Conclusions We found that a working antioxidant machinery takes part in acute stress response and may be differentially affected by other experiences. Given the essential role of stress responsiveness in almost every life process, the identification of the underlying mechanisms and their potential pharmacological modulation add further translational value to our data.

Vincristine (VCR) treatment is often associated to painful neuropathy. Its development is independent from antitumoral mechanism and involves neuroinflammation. We investigated the role of the chemokine prokineticin (PK)2 in a mouse model of VCR induced neuropathy using a PK-receptors (PK-R) antagonist to counteract its development. We also evaluated emotional like deficits in VCR mice. VCR (0,1 mg/kg) was i.p. injected in C57BL/6J male mice once a day for 14 consecutive days. Pain, anxiety and depressive like behaviors were assessed in animals. PK2, PK-Rs, cytokines, neuroinflammatory markers (CD68, CD11b, GFAP, TLR4) and ATF3 were evaluated in DRG, spinal cord, prefrontal cortex and hippocampus. The PK-Rs antagonist PC1, was s.c. injected (150 μg/kg) twice a day from day 7 (hypersensitivity state) until day 14. Its effect on pain and neuroinflammation was evaluated. VCR mice developed neuropathic pain but not mood alterations. After 7 days of VCR treatment we observed a neuroinflammatory condition in DRG with high levels of PK-Rs, TLR4, CD68, ATF3 and IL-1β without relevant alterations in spinal cord. At day 14, an upregulation of PK system and a marked neuroinflammation was evident also in spinal cord. Moreover, at the same time, we observed initial alterations in supraspinal brain areas. PC1 treatment significantly counteracted neuropathic pain and blunted neuroinflammation.

In 2024 the first female astronaut will land on the moon, advancing our preparations for human missions to Mars. While on Earth we are protected from space radiation by our planet's magnetic field, on such deep space voyages astronauts will be exposed to high energy particles from solar flares and galactic cosmic rays (GCR). This exposure carries risks to the central nervous system (CNS) that could jeopardize the mission and astronaut health. Earth-bound studies have employed a variety of single-beam and sequential radiation exposures to simulate the effects of GCR exposure in rodents. Multiple studies have shown that GCR simulation induces a maladaptive activation of microglia - the brain-resident immune cells. GCR simulation also induced synaptic changes resulting in lasting cognitive and behavioral defects. Female and male mice show different susceptibilities to GCR exposure, and evidence suggests this sexually dimorphic response is linked to microglia. Manipulating microglia can prevent the development of cognitive deficits in male mice exposed to components of GCR. This discovery may provide clues towards how to protect astronauts' cognitive and behavioral health both during deep space missions and upon return to Earth.

With increased life expectancy age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition i) rescues intrinsic neuronal electrophysiological properties, ii) restores spine density and iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.ONE SENTENCE SUMMARYInhibition of the integrated stress response restores neuronal and immune dysfunction and alleviates memory deficits in aged mice.

Depression is a recurrent disorder, with about 50% of patients experiencing relapse. Exposure to stressful events may have an adverse impact on the long-term course of the disorder and may alter the response to a subsequent stressor. Indeed, not all the systems impaired by stress may normalize during symptoms remission, facilitating the relapse to the pathology. Hence, we investigated the long-lasting effects of chronic restraint stress (CRS) and its influence on the modifications induced by the exposure to a second hit on brain-derived neurotrophic factor (BDNF) signaling in the prefrontal cortex (PFC). We exposed adult male Sprague Dawley rats to 4 weeks of CRS, we left them undisturbed for the subsequent 3 weeks, and then we exposed animals to one hour of acute restraint stress (ARS). We found that CRS influenced the release of corticosterone induced by ARS and inhibited the ability of ARS to activate mature BDNF, its receptor Tropomyosin receptor kinase B (TRKB), and their associated intracellular cascades: the TRKB-PI3K-AKT), the MEK-MAPK/ERK, and the Phospholipase C &gamma, (PLC&gamma, ) pathways, positively modulated by ARS in non-stressed animals. These results suggest that CRS induces protracted and detrimental consequences that interfere with the ability of PFC to cope with a challenging situation.

One of the most substantial and established environmental risk factors for neurological and psychiatric disorders is stress exposure, whose detrimental consequences hinge on several variables including time. In this regard the gestational period is known to present an intrinsic vulnerability to environmental insults and thus stressful events during pregnancy can lead to severe consequences on the offspring’s brain development with long-term repercussions throughout adulthood. On this basis, we investigated the long-lasting impact of prenatal stress exposure on the susceptibility to the experimental autoimmune encephalomyelitis (EAE), a well-established murine model of multiple sclerosis. Although stress is considered a triggering factor for this chronic, progressive, autoimmune disease, little is known about the underlying mechanisms. To this end, EAE was induced by immunization with MOG35-55/CFA and pertussis toxin administration in adult female C57BL/6 mice born from control or stressed dams exposed to restraint stress during the last days of gestation. Our results demonstrate that gestational stress induces a marked increase in the severity of EAE symptoms in adulthood. Further, we highlight an altered maturation of oligodendrocytes in the spinal cord of prenatally stressed EAE mice, as indicated by the higher levels of GPR17, a marker of immature oligodendrocyte precursor cells. These behavioral and molecular alterations are paralleled by changes in the expression and signaling of the neurotrophin BDNF, an important mediator of neural plasticity that may contribute to stress-induced impaired remyelination. Since several already marketed drugs are able to modulate BDNF levels, these results pave the way to the possibility of repositioning these drugs in multiple sclerosis.

Microglia are the resident immune cells of the central nervous system (CNS). In physiological conditions, microglia contribute to maintaining brain homeostasis by scanning the surrounding parenchyma and acting as scavenger cells. Following different insults to the CNS, microglia turn into a “reactive” state characterized by the production of inflammatory mediators that promote tissue repair to restore homeostasis. Brain insults such as traumatic brain injury, therapeutic brain irradiation and galactic cosmic ray exposure are associated with chronic microglia activation. Chronic microglia activation contributes to injury-related impairments in cognitive functions. Microglia depletion achieved either by pharmacological or genetic techniques represents not only a useful tool for more extensive investigations of microglia roles, but also a potential therapeutic approach to ameliorate or prevent cognitive dysfunctions following brain injury.

Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive. Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia. We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4. Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus. Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug.

Several studies reported that antidepressant drugs have immune-regulatory effects by acting on specific inflammatory mediators. However, considering the highly complex nature of the inflammatory response, we have adopted an unbiased genome-wide strategy to investigate the immune-regulatory activity of the antidepressant agomelatine in modulating the response to an acute inflammatory challenge.Microarray analysis was used to identify genes modulated in the ventral hippocampus of adult rats chronically treated with agomelatine (40 mg/kg, os) before being challenged with a single injection of lipopolysaccharide (LPS; 250 μg/kg, i.p.).The administration of LPS induced the transcription of 284 genes mainly associated with pathways related to the immune/inflammatory system. Agomelatine modulated pathways not only connected to its antidepressant activity, but was also able to prevent the activation of genes induced by LPS. Further comparisons between gene lists of the diverse experimental groups led to the identification of a few transcripts modulated by LPS on which agomelatine has the larger effect of normalisation. Among them, we found the pro-inflammatory cytokine Il-1β and, interestingly, the metabotropic glutamatergic transporter Grm2.These results are useful to better characterise the association between depression and inflammation, revealing new potential targets for pharmacological intervention for depression associated to inflammation.

While neurotransmitter dysfunction represents a key component in mental illnesses, there is now a wide agreement for a central pathophysiological hub that includes hormones, neuroinflammation, redox mechanisms as well as oxidative stress. With respect to oxidation-reduction (redox) mechanisms, preclinical and clinical evidence suggests that an imbalance in the pro/anti-oxidative homeostasis toward the increased production of substances with oxidizing potential may contribute to the etiology and manifestation of different psychiatric disorders. The substantial and continous demand for energy renders the brain highly susceptible to disturbances in its energy supply, especially following exposure to stressful events, which may lead to overproduction of reactive oxygen and nitrogen species under conditions of perturbed antioxidant defenses. This will eventually induce different molecular alterations, including extensive protein and lipid peroxidation, increased blood-brain barrier permeability and neuroinflammation, which may contribute to the changes in brain function and morphology observed in mental illnesses. This view may also reconcile different key concepts for psychiatric disorders, such as the neurodevelopmental origin of these diseases, as well as the vulnerability of selective cellular populations that are critical for specific functional abnormalities. The possibility to pharmacologically modulate the redox system is receiving increasing interest as a novel therapeutic strategy to counteract the detrimental effects of the unbalance in brain oxidative mechanisms. This review will describe the main mechanisms and mediators of the redox system and will examine the alterations of oxidative stress found in animal models of psychiatric disorders as well as in patients suffering from mental illnesses, such as schizophrenia and major depressive disorder. In addition, it will discuss studies that examined the effects of psychotropic drugs, including antipsychotics and antidepressants, on the oxidative balance as well as studies that investigated the effectiveness of a direct modulation of oxidative mechanisms in counteracting the behavioral and functional alterations associated with psychiatric disorders, which supports the promising role of the redox system as a novel therapeutic target for the improved treatment of brain disorders.

Brain resident microglia have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacological depletion of microglia during therapeutic whole-brain irradiation prevents synaptic loss and long-term recognition memory deficits but the mechanisms behind these protective effects are unknown. Here we demonstrate that after a combination of therapeutic whole-brain irradiation and microglia depletion, macrophages originating from circulating monocytes engraft into the brain and replace the microglia pool. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. Brain-engrafted macrophages display reduced phagocytic activity for synaptic compartments compared to microglia from normal brains in response to a secondary concussive brain injury. In addition to sparing mice from brain radiotherapy-induced long-term cognitive deficits, replacement of microglia by brain-engrafted macrophages can prevent concussive injury-induced memory loss. These results demonstrate the long-term functional role of brain-engrafted macrophages as a possible therapeutic tool against radiation-induced cognitive deficits.

Alzheimer’s disease (AD) is the most frequent type of dementia in older people. The complex nature of AD calls for the development of multitarget agents addressing key pathogenic processes. Donepezil, an acetylcholinesterase inhibitor, is a first-line acetylcholinesterase inhibitor used for the treatment of AD. Although several studies have demonstrated the symptomatic efficacy of donepezil treatment in AD patients, the possible effects of donepezil on the AD process are not yet known. In this study, a novel feruloyl–donepezil hybrid compound (PQM130) was synthesized and evaluated as a multitarget drug candidate against the neurotoxicity induced by Aβ1-42 oligomer (AβO) injection in mice. Interestingly, PQM130 had already shown anti-inflammatory activity in different in vivo models and neuroprotective activity in human neuronal cells. The intracerebroventricular (i.c.v.) injection of AβO in mice caused the increase of memory impairment, oxidative stress, neurodegeneration, and neuroinflammation. Instead, PQM130 (0.5–1 mg/kg) treatment after the i.c.v. AβO injection reduced oxidative damage and neuroinflammation and induced cell survival and protein synthesis through the modulation of glycogen synthase kinase 3β (GSK3β) and extracellular signal–regulated kinases (ERK1/2). Moreover, PQM130 increased brain plasticity and protected mice against the decline in spatial cognition. Even more interesting is that PQM130 modulated different pathways compared to donepezil, and it is much more effective in counteracting AβO damage. Therefore, our findings highlighted that PQM130 is a potent multi-functional agent against AD and could act as a promising neuroprotective compound for anti-AD drug development.

Psychiatric disorders represent a critical challenge to our society, given their high global prevalence, complex symptomatology, elusive etiology and the variable effectiveness of pharmacological therapies. Recently, there has been a shift in investigating and redefining these diseases by integrating behavioral observations and multilevel neurobiological measures. Accordingly, endophenotype-oriented studies are needed to develop new therapeutic strategies, with the idea of targeting shared symptoms instead of one defined disease. With these premises, here we investigated the therapeutic properties of chronic treatment with the second-generation antipsychotic blonanserin in counteracting the alterations caused by 7 weeks of Chronic Mild Stress (CMS) in the rat. CMS is a well-established preclinical model able to induce depressive and anxiety-like alterations, which are shared by different psychiatric disorders. Our results demonstrated that the antipsychotic treatment normalizes the CMS-induced emotionality deficits, an effect that may be due to its ability in modulating, within the prefrontal cortex, redox mechanisms, a molecular dysfunction associated with several psychiatric disorders. These evidences provide new insights into the therapeutic properties and potential use of blonanserin as well as in its mechanisms of action and provide further support for the role of oxidative stress in the pathophysiology of psychiatric disorders.

Population aging is accelerating rapidly worldwide, from 461 million people older than 65 years in 2004 to an estimated 2 billion people by 2050, leading to critical implications for the planning and delivery of health and social care.:The most problematic expression of population aging is the clinical condition of frailty, which is a state of increased vulnerability that develops as a consequence of the accumulation of microscopic damages in many physiological systems that lead to a striking and disproportionate change in health state, even after an apparently small insult.:Since little is known about the biology of frailty, an important perspective to understand this phenomenon is to establish how the alterations that physiologically occur during a condition of healthy aging may instead promote cumulative decline with subsequent depletion of homoeostatic reserve and increase the vulnerability also after minor stressor events.:In this context, the present review aims to provide a description of the molecular mechanisms that, by having a critical impact on behavior and neuronal function in aging, might be relevant for the development of frailty. Moreover, since these biological systems are also involved in the coping strategies set in motion to respond to environmental challenges, we propose a role for lifestyle stress as an important player to drive frailty in aging.

Traumatic brain injury (TBI) is of particular concern for the aging community since there is both increased incidence of TBI and decreased functional recovery in this population. In addition, TBI is the strongest environmental risk factor for development of Alzheimer&rsquo, s disease and other dementia-related neurodegenerative disorders. Critical changes that affect cognition take place over time following the initial insult. Our previous work identified immune system activation as a key contributor to cognitive deficits observed in aged animals. Using a focal contusion model in the current study, we demonstrate a brain lesion and cavitation formation, as well as prolonged blood&ndash, brain barrier breakdown. These changes were associated with a prolonged inflammatory response, characterized by increased microglial cell number and phagocytic activity 30 days post injury, corresponding to significant memory deficits. We next aimed to identify the injury-induced cellular and molecular changes that lead to chronic cognitive deficits in aged animals, and measured increases in complement initiation components C1q, C3, and CR3, which are known to regulate microglial&ndash, synapse interactions. Specifically, we found significant accumulation of C1q on synapses within the hippocampus, which was paralleled by synapse loss 30 days post injury. We used genetic and pharmacological approaches to determine the mechanistic role of complement initiation on cognitive loss in aging animals after TBI. Notably, both genetic and pharmacological blockade of the complement pathway prevented memory deficits in aged injured animals. Thus, therapeutically targeting early components of the complement cascade represents a significant avenue for possible clinical intervention following TBI in the aging population.

Microglia are the main immune component in the brain that can regulate neuronal health and synapse function. Exposure to cosmic radiation can cause long-term cognitive impairments in rodent models thereby presenting potential obstacles for astronauts engaged in deep space travel. The mechanism/s for how cosmic radiation induces cognitive deficits are currently unknown. We find that temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. Gene array profiling reveals that acute microglia depletion alters the late neuroinflammatory response to cosmic radiation. The repopulated microglia present a modified functional phenotype with reduced expression of scavenger receptors, lysosome membrane protein and complement receptor, all shown to be involved in microglia-synapses interaction. The lower phagocytic activity observed in the repopulated microglia is paralleled by improved synaptic protein expression. Our data provide mechanistic evidence for the role of microglia in the development of cognitive deficits after cosmic radiation exposure.

Background Psychiatric disorders are associated with altered function of inhibitory neurotransmission within the limbic system, which may be due to the vulnerability of selective neuronal subtypes to challenging environmental conditions, such as stress. In this context, parvalbumin-positive GABAergic interneurons, which are critically involved in processing complex cognitive tasks, are particularly vulnerable to stress exposure, an effect that may be the consequence of dysregulated redox mechanisms. Methods Adult Male Wistar rats were subjected to the chronic mild stress procedure for 7 weeks. After 2 weeks, both control and stress groups were further divided into matched subgroups to receive chronic administration of vehicle or lurasidone (3 mg/kg/d) for the subsequent 5 weeks. Using real-time RT-PCR and western blot, we investigated the expression of GABAergic interneuron markers and the levels of key mediators of the oxidative balance in the dorsal and ventral hippocampus. Results Chronic mild stress induced a specific decrease of parvalbumin expression in the dorsal hippocampus, an effect normalized by lurasidone treatment. Interestingly, the regulation of parvalbumin levels was correlated to the modulation of the antioxidant master regulator NRF2 and its chaperon protein KEAP1, which were also modulated by pharmacological intervention. Conclusions Our findings suggest that the susceptibility of parvalbumin neurons to stress may represent a key mechanism contributing to functional and structural impairments in specific brain regions relevant for psychiatric disorders. Moreover, we provide new insights on the mechanism of action of lurasidone, demonstrating that its chronic treatment normalizes chronic mild stress-induced parvalbumin alterations, possibly by potentiating antioxidant mechanisms, which may ameliorate specific functions that are deteriorated in psychiatric patients.

Background Primary central nervous system (CNS) neoplasms and brain metastases are routinely treated with whole-brain radiation. Long-term survival occurs in many patients, but their quality of life is severely affected by the development of cognitive deficits, and there is no treatment to prevent these adverse effects. Neuroinflammation, associated with activation of brain-resident microglia and infiltrating monocytes, plays a pivotal role in loss of neurological function and has been shown to be associated with acute and long-term effects of brain irradiation. Colony-stimulating factor 1 receptor (CSF-1R) signaling is essential for the survival and differentiation of microglia and monocytes. Here, we tested the effects of CSF-1R blockade by PLX5622 on cognitive function in mice treated with three fractions of 3.3 Gy whole-brain irradiation. Methods Young adult C57BL/6J mice were given three fractions of 3.3 Gy whole-brain irradiation while they were on diet supplemented with PLX5622, and the effects on periphery monocyte accumulation, microglia numbers, and neuronal functions were assessed. Results The mice developed hippocampal-dependent cognitive deficits at 1 and 3 months after they received fractionated whole-brain irradiation. The impaired cognitive function correlated with increased number of periphery monocyte accumulation in the CNS and decreased dendritic spine density in hippocampal granule neurons. PLX5622 treatment caused temporary reduction of microglia numbers, inhibited monocyte accumulation in the brain, and prevented radiation-induced cognitive deficits. Conclusions Blockade of CSF-1R by PLX5622 prevents fractionated whole-brain irradiation-induced memory deficits. Therapeutic targeting of CSF-1R may provide a new avenue for protection from radiation-induced memory deficits. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0671-y) contains supplementary material, which is available to authorized users.

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Background Exposure of rodents to chronic stress is able to recapitulate a number of functional alterations that are associated with psychiatric disorders, including anhedonia and cognitive impairment. Stress-based experimental models are also useful to investigate the ability of pharmacological intervention in normalizing such defects as well as the molecular alterations associated with the behavioral phenotype. On these bases, the aim of the present study was to investigate the ability of a chronic treatment with the multi-receptor modulator lurasidone in normalizing behavioral changes produced by chronic mild stress (CMS) in rats. Moreover, we investigated the potential contribution of parvalbumin expression and of redox mechanisms in the alterations brought about by CMS exposure. Methods Adult male Wistar rats were exposed to CMS for 2 weeks and sucrose consumption was used to identify rats that were susceptible to the stressful manipulation. Control and CMS-susceptible rats were then randomized to receive chronic vehicle or the multi-receptor modulator lurasidone (3 mg/kg/day) for 5 more weeks, while continuing the stress procedure. Animals were tested for anhedonia, using the sucrose intake test, and for cognitive impairment, using the novel object recognition (NOR) test. Rats were sacrificed at the end of the procedures and the brain regions of interest were dissected and used for the molecular analyses. Results Exposure to CMS produced a persistent anhedonic phenotype as well as a significant deficit in the NOR test. Both behavioral abnormalities were normalized by chronic lurasidone treatment. Rats exposed to CMS display a marked and selective reduction in the expression of parvalbumin, which identifies a subpopulation of GABAergic interneurons, in dorsal (but not ventral) hippocampus, an effect that was normalized by chronic lurasidone administration. CMS rats also show a significant up-regulation of (NADPH) oxidase 2 (NOX2), which is critically involved in oxidative stress, as well as a down-regulation of Nrf-2, a master regulator of antioxidant defense. These alterations in dorsal hippocampus were normalized in animals that received chronic lurasidone treatment that was also capable of reducing the levels of Keap-1, an important player that exerts a repressive control over Nrf-2. Discussion Our results demonstrate the ability of lurasidone in normalizing anhedonia and cognitive deficits associated with CMS exposure, suggesting its effectiveness on different ‘domains’ (RDoC) that characterize psychiatric disorders. Lurasidone was also able to normalize the effects produced by CMS exposure on parvalbumin expression, possibly through its ability in promoting anti-oxidative mechanisms within the dorsal hippocampus. All in all, these effects may promote resilience toward the alterations produced by adverse environmental conditions, such as stress, which represents a major vulnerability element in the etiology of psychiatric disorders.

Major depression is a complex disease that originates from the interaction between a genetic background of susceptibility and environmental factors such as stress. At molecular level, it is characterized by dysfunctions of multiple systems including neurotransmitters, hormones, signalling pathways, neurotrophic and neuroplastic molecules and - more recently - inflammatory mediators. Accordingly, in the present study we used the chronic mild stress (CMS) paradigm in the rat to elucidate to what extent brain inflammation may contribute to the development and/or the maintenance of an anhedonic phenotype and how pharmacological intervention may interfere with such behavioral and molecular stress-induced alterations. To this aim, adult male rats were exposed to CMS for 2 weeks and the cerebral expression of several mediators of the inflammatory system was evaluated in the hippocampus and prefrontal cortex of both stressed and control animals in parallel with the sucrose intake. Next, the animals that showed a decreased sucrose consumption were exposed to five further weeks of CMS and treated with the antidepressants imipramine or agomelatine, or the antipsychotic lurasidone. Our results demonstrate that only the stressed animals that were characterized by a deficit in sucrose intake showed increased expression of the pro-inflammatory cytokines IL-1β, IL-6 and up-regulation of markers and mediators of microglia activation such as CD11b, CX3CL1 and its receptor CX3CR1 in comparison with stress-resilient animals. Some of these molecular alterations persisted also after longer stress exposure and were modulated, similarly to the behavioral effects of CMS, by chronic pharmacological treatment. These data suggest that neuroinflammation may have a key role in the pathological consequences of stress exposure, thus contributing to the subject's vulnerability for depression.