Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers.

Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.

Association between NTRK2 Polymorphisms, Hippocampal Volumes and Treatment Resistance in Major Depressive Disorder.

Despite the increasing availability of antidepressant drugs, a high rate of patients with major depression (MDD) does not respond to pharmacological treatments. Brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling is thought to influence antidepressant efficacy and hippocampal volumes, robust predictors of treatment resistance. We therefore hypothesized the possible role of BDNF and neurotrophic receptor tyrosine kinase 2 (NTRK2)-related polymorphisms in affecting both hippocampal volumes and treatment resistance in MDD. A total of 121 MDD inpatients underwent 3T structural MRI scanning and blood sampling to obtain genotype information. General linear models and binary logistic regressions were employed to test the effect of genetic variations related to BDNF and NTRK2 on bilateral hippocampal volumes and treatment resistance, respectively. Finally, the possible mediating role of hippocampal volumes on the relationship between genetic markers and treatment response was investigated. A significant association between one NTRK2 polymorphism with hippocampal volumes and antidepressant response was found, with significant indirect effects. Our results highlight a possible mechanistic explanation of antidepressant action, possibly contributing to the understanding of MDD pathophysiology.

The Dysfunctional Mechanisms Throwing Tics: Structural and Functional Changes in Tourette Syndrome.

Tourette Syndrome (TS) is a high-incidence multifactorial neuropsychiatric disorder characterized by motor and vocal tics co-occurring with several diverse comorbidities, including obsessive-compulsive disorder and attention-deficit hyperactivity disorder. The origin of TS is multifactorial, with strong genetic, perinatal, and immunological influences. Although almost all neurotransmettitorial systems have been implicated in TS pathophysiology, a comprehensive neurophysiological model explaining the dynamics of expression and inhibition of tics is still lacking. The genesis and maintenance of motor and non-motor aspects of TS are thought to arise from functional and/or structural modifications of the basal ganglia and related circuitry. This complex wiring involves several cortical and subcortical structures whose concerted activity controls the selection of the most appropriate reflexive and habitual motor, cognitive and emotional actions. Importantly, striatal circuits exhibit bidirectional forms of synaptic plasticity that differ in many respects from hippocampal and neocortical plasticity, including sensitivity to metaplastic molecules such as dopamine. Here, we review the available evidence about structural and functional anomalies in neural circuits which have been found in TS patients. Finally, considering what is known in the field of striatal plasticity, we discuss the role of exuberant plasticity in TS, including the prospect of future pharmacological and neuromodulation avenues.

Exploiting the molecular diversity of the synapse to investigate neuronal communication: A guide through the current toolkit.

Chemical synapses are tiny and overcrowded environments, deeply embedded inside brain tissue and enriched with thousands of protein species. Many efforts have been devoted to developing custom approaches for evaluating and modifying synaptic activity. Most of these methods are based on the engineering of one or more synaptic protein scaffolds used to target active moieties to the synaptic compartment or to manipulate synaptic functioning. In this review, we summarize the most recent methodological advances and provide a description of the involved proteins as well as the operation principle. Furthermore, we highlight their advantages and limitations in relation to studies of synaptic transmission in vitro and in vivo. Concerning the labelling methods, the most important challenge is how to extend the available approaches to the in vivo setting. On the other hand, for those methods that allow manipulation of synaptic function, this limit has been overcome using optogenetic approaches that can be more easily applied to the living brain. Finally, future applications of these methods to neuroscience, as well as new potential routes for development, are discussed.

Occlusion of dopamine-dependent synaptic plasticity in the prefrontal cortex mediates the expression of depressive-like behavior and is modulated by ketamine.

Unpredictable chronic mild stress (CMS) is among the most popular protocols used to induce depressive-like behaviors such as anhedonia in rats. Differences in CMS protocols often result in variable degree of vulnerability, and the mechanisms behind stress resilience are of great interest in neuroscience due to their involvement in the development of psychiatric disorders, including major depressive disorder. Expression of depressive-like behaviors is likely driven by long-term alterations in the corticolimbic system and by downregulation of dopamine (DA) signaling. Although we have a deep knowledge about the dynamics of tonic and phasic DA release in encoding incentive salience and in response to acute/chronic stress, its modulatory action on cortical synaptic plasticity and the following implications on animal behavior remain elusive. Here, we show that the expression of DA-dependent synaptic plasticity in the medial prefrontal cortex (mPFC) is occluded in rats vulnerable to CMS, likely reflecting differential expression of AMPA receptors. Interestingly, such difference is not observed when rats are acutely treated with sub-anesthetic ketamine, possibly through the recruitment of dopaminergic nuclei such as the ventral tegmental area. In addition, by applying the synaptic activity sensor SynaptoZip in vivo, we found that chronic stress unbalances the synaptic drive from the infralimbic and prelimbic subregions of the mPFC toward the basolateral amygdala, and that this effect is counteracted by ketamine. Our results provide novel insights into the neurophysiological mechanisms behind the expression of vulnerability to stress, as well as behind the antidepressant action of ketamine.

Synaptic plasticity mechanisms behind TMS efficacy: insights from its application to animal models.

Neural plasticity is defined as a reshape of communication paths among neurons, expressed through changes in the number and weights of synaptic contacts. During this process, which occurs massively during early brain development but continues also in adulthood, specific brain functions are modified by activity-dependent processes, triggered by external as well as internal stimuli. Since transcranial magnetic stimulation (TMS) produces a non-invasive form of brain cells activation, many different TMS protocols have been developed to treat neurological and psychiatric conditions and proved to be beneficial. Although neural plasticity induction by TMS has been widely assessed on human subjects, we still lack compelling evidence about the actual biological and molecular mechanisms. To support a better comprehension of the involved phenomena, the main focus of this review is to summarize what has been found through the application of TMS to animal models. The hope is that such integrated view will shed light on why and how TMS so effectively works on human subjects, thus supporting a more efficient development of new protocols in the future.

Activity-based anorexia animal model: a review of the main neurobiological findings.

BACKGROUND: The genesis of anorexia nervosa (AN), a severe eating disorder with a pervasive effect on many brain functions such as attention, emotions, reward processing, cognition and motor control, has not yet been understood. Since our current knowledge of the genetic aspects of AN is limited, we are left with a large and diversified number of biological, psychological and environmental risk factors, called into question as potential triggers of this chronic condition with a high relapse rate. One of the most valid and used animal models for AN is the activity-based anorexia (ABA), which recapitulates important features of the human condition. This model is generated from naïve rodents by a self-motivated caloric restriction, where a fixed schedule food delivery induces spontaneous increased physical activity. AIM: In this review, we sought to provide a summary of the experimental research conducted using the ABA model in the pursuit of potential neurobiological mechanism(s) underlying AN. METHOD: The experimental work presented here includes evidence for neuroanatomical and neurophysiological changes in several brain regions as well as for the dysregulation of specific neurochemical synaptic and neurohormonal pathways. RESULTS: The most likely hypothesis for the mechanism behind the development of the ABA phenotype relates to an imbalance of the neural circuitry that mediates reward processing. Evidence collected here suggests that ABA animals show a large set of alterations, involving regions whose functions extend way beyond the control of reward mechanisms and eating habits. Hence, we cannot exclude a primary role of these alterations from a mechanistic theory of ABA induction. CONCLUSIONS: These findings are not sufficient to solve such a major enigma in neuroscience, still they could be used to design ad hoc further experimental investigation. The prospect is that, since treatment of AN is still challenging, the ABA model could be more effectively used to shed light on the complex AN neurobiological framework, thus supporting the future development of therapeutic strategies but also the identification of biomarkers and diagnostic tools. Anorexia Nervosa (AN) is a severe eating disorder with a dramatic effect on many functions of our brain, such as attention, emotions, cognition and motion control. Since our current knowledge of the genetic aspects behind the development of AN is still limited, many biological, psychological and environmental factors must be taken into account as potential triggers of this condition. One of the most valid animal models for studying AN is the activity-based anorexia (ABA). In this model, rodents spontaneously limit food intake and start performing increased physical activity on a running wheel, a result of the imposition of a fixed time schedule for food delivery. In this review, we provide a detailed summary of the experimental research conducted using the ABA model, which includes extended evidence for changes in the anatomy and function of the brain of ABA rodents. The hope is that such integrated view will support the design of future experiments that will shed light on the complex brain mechanisms behind AN. Such advanced knowledge is crucial to find new, effective strategies for both the early diagnosis of AN and for its treatment.

A novel integrated approach to estimate the mitochondrial content of neuronal cells and brain tissues.

BACKGROUND: Mitochondria and their dynamics fuel most cellular processes both in physiological and pathological conditions. In the central nervous system, mitochondria sustain synaptic transmission and plasticity via multiple mechanisms which include their redistribution and/or expansion to higher energy demanding sites, sustaining activity changes and promoting morphological circuit adaptations. NEW METHOD: To be able to evaluate changes in mitochondrial number and protein phenotype, we propose a novel methodological approach where the simultaneous analysis of both mitochondrial DNA and protein content is performed on each individual microsample, avoiding non-homogeneous loss of material. RESULTS: We validated this method on neuronal-like cells and tissue samples and obtained estimates for the mitochondrial/genomic DNA ratio as well as for the abundance of protein counterparts. When the mitochondrial content per cell was evaluated in different brain areas, our results matched the known regional variation in aerobic-anaerobic metabolism. When long-term potentiation (LTP) was induced on hippocampal neurons, we detected increases in the abundance of mitochondria that correlated with the degree of synaptic enhancement. CONCLUSIONS: Our approach can be effectively used to study the mitochondrial content andits changes in different brain cells and tissues.

Functional mapping of brain synapses by the enriching activity-marker SynaptoZip.

Ideally, elucidating the role of specific brain circuits in animal behavior would require the ability to measure activity at all involved synapses, possibly with unrestricted field of view, thus even at those boutons deeply located into the brain. Here, we introduce and validate an efficient scheme reporting synaptic vesicle cycling in vivo. This is based on SynaptoZip, a genetically encoded molecule deploying in the vesicular lumen a bait moiety designed to capture upon exocytosis a labeled alien peptide, Synbond. The resulting signal is cumulative and stores the number of cycling events occurring at individual synapses. Since this functional signal is enduring and measurable both online and ex post, SynaptoZip provides a unique method for the analysis of the history of synaptic activity in regions several millimeters below the brain surface. We show its broad applicability by reporting stimulus-evoked and spontaneous circuit activity in wide cortical fields, in anesthetized and freely moving animals.

Bacteriophages and Their Immunological Applications against Infectious Threats.

Bacteriophage therapy dates back almost a century, but the discovery of antibiotics led to a rapid decline in the interests and investments within this field of research. Recently, the novel threat of multidrug-resistant bacteria highlighted the alarming drop in research and development of new antibiotics: 16 molecules were discovered during 1983-87, 10 new therapeutics during the nineties, and only 5 between 2003 and 2007. Phages are therefore being reconsidered as alternative therapeutics. Phage display technique has proved to be extremely promising for the identification of effective antibodies directed against pathogens, as well as for vaccine development. At the same time, conventional phage therapy uses lytic bacteriophages for treatment of infections and recent clinical trials have shown great potential. Moreover, several other approaches have been developed in vitro and in vivo using phage-derived proteins as antibacterial agents. Finally, their use has also been widely considered for public health surveillance, as biosensor phages can be used to detect food and water contaminations and prevent bacterial epidemics. These novel approaches strongly promote the idea that phages and their proteins can be exploited as an effective weapon in the near future, especially in a world which is on the brink of a "postantibiotic era."