Here we discuss the role of diverse environmental manipulations affecting cognition with special regard to psychiatric conditions. We present evidence supporting a direct causal correlation between the valence of the environmental stimulation and some psychopathological traits and how the environment influences brain structure and function with special regard to oxidative stress and mitochondrial activity. Increasing experimental evidence supports a role for mitochondrial dysfunctions in neuropsychiatric disorders. Brain mitochondria are considered crucial mediators of allostasis, that is the capability to adapt to stress via a complex interaction between the autonomic, metabolic, and immune systems to maintain cellular homeostasis. In this process, mitochondria act as highly dynamic integrators by sensing and transducing stressors into adaptation mechanisms via metabolic stress mediators, such as glucocorticoids and catecholamines. Alterations in cellular homeostasis induced by chronic stress are thought to predispose to disease by triggering the so-called "mitochondrial allostatic load". This process is characterized by functional and structural changes of the mitochondria, ultimately leading to oxidative stress, inflammation, mitochondrial DNA damage and apoptosis. In this review we discuss the role of diverse environmental manipulations to affect cognition with special regard to psychiatric conditions. How the environment influences brain structure and function, and the interactions between rearing conditions, oxidative stress and mitochondrial activity are fundamental questions that are still poorly understood. As will be discussed, increasing experimental evidence supports a role for mitochondrial dysfunctions in neuropsychiatric disorders. Brain mitochondria are considered crucial mediators of allostasis, that is the capability to adapt to stress via a complex interaction between the autonomic, metabolic, and immune systems to maintain cellular homeostasis. In this process, mitochondria act as highly dynamic integrators by sensing and transducing stressors into adaptation mechanisms via metabolic stress mediators, such as glucocorticoids and catecholamines. Alterations in cellular homeostasis induced by chronic stress are thought to predispose to disease by triggering the so-called "mitochondrial allostatic load". This process is characterized by functional and structural changes of the mitochondria, ultimately leading to oxidative stress, inflammation, mitochondrial DNA damage and apoptosis. The brain requires considerable mitochondrial reserve not only to sustain basal neuronal needs but also to provide increasing energy demands during stress. Consistently with these high energetic requirements, it is reasonable to hypothesise that the brain is particularly vulnerable to mitochondrial defects. Thus, even subtle metabolic alterations might have a substantial impact on cognitive functions. Over the last decade, several experimental evidence supported the hypothesis that a suboptimal mitochondrial function, which could be of genetic origin or acquired following adverse life events, is a key vulnerability factor for stress-related psychopathologies. Chronic psychological stress is a major promoter of anxiety as well as of oxidative damage, as shown in several studies. Recent evidence from mouse models harbouring mutations in mitochondrial genes demonstrated the role of mitochondria in modulating the response to acute psychological stress. However, it has yet to be determined whether mitochondrial dysfunctions are the cause or the consequence of anxiety. In this review, we discuss how adverse psychosocial environments can impact mitochondrial bioenergetics at the molecular level and we gather evidence from several studies linking energy metabolism and stress resilience/vulnerability. Moreover, we review recent findings supporting that metabolic dysfunction can underlie deficits in complex social behaviours. As will be discussed, aberrations in mitochondrial functionality have been found in the nucleus accumbens of highly anxious mice and mediate low social competitiveness. In addition, alterations in sociability can be reversed by enhancing mitochondrial functions. Recent evidence also demonstrated that a specific mutation in mitochondrial DNA, previously linked to autism spectrum disorder, produces autistic endophenotypes in mice by altering respiration chain and reactive oxygen species (ROS) production. Finally, we discuss a "Negative Enrichment" model that can explain some of the psychopathological conditions relevant to humans. Evidence of a direct causal correlation of valence of environmental stimulation and psychopathological traits will be presented, and possible molecular mechanisms that focus on oxidative stress. Collectively, the findings described here have been achieved with a wide set of behavioural and cognitive tasks with translational validity. Thus, they will be useful for future work aimed to elucidate the fine metabolic alterations in psychopathologies and devise novel approaches targeting mitochondria to alleviate these conditions.

The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the 16p11.2 deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in 16p11.2 deletion carriers. SIGNIFICANCE STATEMENT The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the 16p11.2 chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the 16p11.2del mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult 16p11.2del mice. These data provide a strong rationale for therapeutic approaches to this disorder.

The basal ganglia play a critical role in shaping motor behavior. For this function, the activity of medium spiny neurons (MSNs) of the striatonigral and striatopallidal pathways must be integrated. It remains unclear whether the activity of the two pathways is primarily coordinated by synaptic plasticity mechanisms. Using a model of Parkinson's disease, we determined the circuit and behavioral effects of concurrently regulating cell-type-specific forms of corticostriatal long-term synaptic depression (LTD) by inhibiting small-conductance Ca(2+)-activated K(+) channels (SKs) of the dorsolateral striatum. At striatopallidal synapses, SK channel inhibition rescued the disease-linked deficits in endocannabinoid (eCB)-dependent LTD. At striatonigral cells, inhibition of these channels counteracted a form of adenosine-mediated LTD by activating the ERK cascade. Interfering with eCB-, adenosine-, and ERK signaling in vivo alleviated motor abnormalities, which supports that synaptic modulation of striatal pathways affects behavior. Thus, our results establish a central role of coordinated synaptic plasticity at MSN subpopulations in motor control.

Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction.

Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5‐mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2‐ERK1/2 interactions.