Exploring genetic influences on cognition: emerging strategies for target validation and treatment optimization

Genomic research has produced an abundance of new candidate targets that remain to be validated as potential treatments for neuropsychiatric disorders. Functional neuroimaging, meanwhile, has provided detailed new insights into the neural circuits involved in emotional and cognitive control. At the growing interface between these independent lines of progress, new efforts are underway to unify our understanding of regional brain function with that of genetic and biochemical influences on behavior. Such a unified understanding of the mechanisms involved in cognitive and emotional control may open up new avenues for therapeutic intervention at the pharmacological and behavioral levels. In line with this, a new initiative sponsored by the National Institutes of Mental Health (NIMH) aims to bridge gaps between clinical diagnostics and the molecular processes that influence susceptibility to psychiatric disorders. A major goal of this initiative is to identify the neural and neurochemical substrates of basic cognitive processes that are disrupted in psychiatric disorders and to examine the influence of genetic factors at the cognitive level. This review describes some well-known findings that are at the forefront of this interface. The progress already made indicates that the goals of the new initiative are well founded and achievable.     

Animal models of psychiatric disorder and their validity--from the perspective of behavioral pharmacology

Animal models of psychiatric disorders are indispensable tools to gain insights into neural mechanisms underlying these disorders and to assess potential therapeutic actions of novel compounds in preclinical settings. However, it is difficult to establish appropriate animal models for these disorders because there is no proof on whether or not what occurs in the animal brain is comparable to what occurs in the human brain. The initial development of animal models of psychiatric disorders is often based on "face validity" as reflected in the similarity of behavioral signs and symptoms observed in humans and animal and subsequently based on "construct validity" as measured by strong correlation in behaviors and neural events between the animal model and patients of the disorder. The practical value of such animal models is reflected ultimately in their "predictive validity" in predicting the therapeutic efficacy of new treatments for psychiatric disorders. The present review will focus on animal models of schizophrenia and depression by the use of mainly environmental stress and pharmacological treatments, which are expected to induce signs and symptoms analogous to those of patients with such disorders.     

Neural networks in psychiatry

Over the past three decades numerous imaging studies have revealed structural and functional brain abnormalities in patients with neuropsychiatric diseases. These structural and functional brain changes are frequently found in multiple, discrete brain areas and may include frontal, temporal, parietal and occipital cortices as well as subcortical brain areas. However, while the structural and functional brain changes in patients are found in anatomically separated areas, these are connected through (long distance) fibers, together forming networks. Thus, instead of representing separate (patho)-physiological entities, these local changes in the brains of patients with psychiatric disorders may in fact represent different parts of the same ‘elephant’, i.e., the (altered) brain network. Recent developments in quantitative analysis of complex networks, based largely on graph theory, have revealed that the brain's structure and functions have features of complex networks. Here we briefly introduce several recent developments in neural network studies relevant for psychiatry, including from the 2013 special issue on Neural Networks in Psychiatry in European Neuropsychopharmacology. We conclude that new insights will be revealed from the neural network approaches to brain imaging in psychiatry that hold the potential to find causes for psychiatric disorders and (preventive) treatments in the future.     

Experimental models for anxiolytic drug discovery in the era of omes and omics

Introduction: Animal behavioral models have become an indispensable tool for studying anxiety disorders and testing anxiety-modulating drugs. However, significant methodological and conceptual challenges affect the translational validity and accurate behavioral dissection in such models. They are also often limited to individual behavioral domains and fail to target the disorder's real clinical picture (its spectrum or overlap with other disorders), which hinder screening and development of novel anxiolytic drugs. Areas covered: In this article, the authors discuss and emphasize the importance of high-throughput multi-domain neurophenotyping based on the latest developments in video-tracking and bioinformatics. Additionally, the authors also explain how bioinformatics can provide new insight into the neural substrates of brain disorders and its benefit for drug discovery. Expert opinion: The throughput and utility of animal models of anxiety and other brain disorders can be markedly increased by a number of ways: i) analyzing systems of several domains and their interplay in a wider spectrum of model species; ii) using a larger number of end points generated by video-tracking tools; iii) correlating behavioral data with genomic, proteomic and other physiologically relevant markers using online databases and iv) creating molecular network-based models of anxiety to identify new targets for drug design and discovery. Experimental models utilizing bioinformatics tools and online databases will not only improve our understanding of both gene-behavior interactions and complex trait interconnectivity but also highlight new targets for novel anxiolytic drugs.     

Research update: neurogenesis in adult brain and neuropsychiatric disorders

Until recently neurogenesis in mammals was considered to occur only during the embryonic and early post-natal periods and to have no significant role in the adult nervous system. However, it is now accepted that neurogenesis occurs in two brain regions in adult mammals, namely, the hippocampus and olfactory bulb. In both regions new neurons arise from a resident population of neural progenitor cells that are maintained throughout adult life. Hippocampal neurogenesis is required for some types of hippocampal-dependent learning. Many factors enhance hippocampal neurogenesis including hormones, growth factors, drugs, neurotransmitters, and physical exercise as well as learning a hippocampal-dependent task. Other factors suppress hippocampal neurogenesis; these include aging, stress, glucocorticoids and stimuli that activate the pituitary/adrenal axis. Recently much attention has become focused on the relevance of hippocampal neurogenesis to the pathophysiology and treatment of mood disorders. Indeed all major pharmacological and non-pharmacological treatments for depression enhance hippocampal neurogenesis and suppressing hippocampal neurogenesis in mice blocks behavioral responses in some antidepressant-sensitive tests. Altered hippocampal neurogenesis may also play a pathophysiological role in neurodegenerative disorders such as Alzheimer's disease. How much neurogenesis occurs normally in other brain regions is unclear. Neural progenitors are found throughout the neuraxis including both neurogenic and non-neurogenic regions. When cultured in vitro or isolated and transplanted back into neurogenic brain regions, these cells can differentiate into neurons although in their in situ location they seem to behave as lineage-restricted glial progenitors. The environmental cues that limit the potential of progenitor cells in non-neurogenic brain regions are unknown. However, an emerging view is that astrocytes, a subset of which also functions as neural progenitor cells, are critical in regulating the local environment. After transplantation into adult brain, neural stem cells are capable of surviving and differentiating into both neurons and glial cells, offering hope that stem cell therapy may be utilized to treat a variety of neurological and perhaps psychiatric disorders. The widespread existence of endogenous neural progenitors even in non-neurogenic brain regions also offers hope that the potential of these cells may be harnessed to repair cellular injuries caused by injuries such as stroke, trauma or neurodegenerative diseases. While obstacles remain to both approaches, stem-cell-based therapies remain an area of intense research interest.     

Role of cytokines in psychopathology: therapeutic implications

Cytokines can influence physiological functions such as sleep and food intake; they also interact with a number of neurotransmitters and second messengers in the brain. Cytokines are involved in a number of infectious, inflammatory, neoplastic, metabolic and degenerative illnesses. They also have been implicated in some psychiatric disorders, including 1) depressive and anxiety disorders; 2) schizophrenic disorders (chronic and acute); 3) autistic disorder; 4) eating disorders; and 5) obsessive-compulsive disorder. Alterations in cytokine peptide/receptor production or function in major psychiatric disorders are of special interest to researchers in the field. Exogenous administration of cytokines may be of therapeutic value in disorders in which the cytokine system may be disturbed. In some brain disorders of defined neuropathology, some cytokines have been found clinically useful. Such a development has yet to occur in the treatment of psychiatric disorders; however, some limited and very preliminary observations suggest that manipulation of the cytokine network may be of potential value in the treatment of some psychiatric disorders. Considering the human and economic costs of major psychiatric disorders, alteration of the cytokine network as a potential therapeutic tool is worthy of consideration and investigation.     

Experimental models for anxiolytic drug discovery in the era of omes and omics

Introduction: Animal behavioral models have become an indispensable tool for studying anxiety disorders and testing anxiety-modulating drugs. However, significant methodological and conceptual challenges affect the translational validity and accurate behavioral dissection in such models. They are also often limited to individual behavioral domains and fail to target the disorder's real clinical picture (its spectrum or overlap with other disorders), which hinder screening and development of novel anxiolytic drugs.

Areas covered: In this article, the authors discuss and emphasize the importance of high-throughput multi-domain neurophenotyping based on the latest developments in video-tracking and bioinformatics. Additionally, the authors also explain how bioinformatics can provide new insight into the neural substrates of brain disorders and its benefit for drug discovery.

Expert opinion: The throughput and utility of animal models of anxiety and other brain disorders can be markedly increased by a number of ways: i) analyzing systems of several domains and their interplay in a wider spectrum of model species; ii) using a larger number of end points generated by video-tracking tools; iii) correlating behavioral data with genomic, proteomic and other physiologically relevant markers using online databases and iv) creating molecular network-based models of anxiety to identify new targets for drug design and discovery. Experimental models utilizing bioinformatics tools and online databases will not only improve our understanding of both gene–behavior interactions and complex trait interconnectivity but also highlight new targets for novel anxiolytic drugs.     

Role of central glutamatergic neurotransmission in the pathogenesis of psychiatric and behavioral disorders

Glutamate is the most ubiquitous of the fast excitatory neurotransmitters in the central nervous system. In the process, glutamate fulfills numerous physiological functions, but also plays an important role in the pathophysiology of a variety of psychiatric and behavioral disorders such as schizophrenia. Recently, modulation of glutamatergic neurotransmission has been suggested to be involved in the mechanisms of action of antipsychotic drugs. Thus, pharmacological manipulation of glutamatergic transmission may be a feasible therapeutic strategy for treatment of schizophrenia. In this review article, we focus on the role of central glutamatergic neurotransmission in the pathogenesis and pharmacotherapy of schizophrenia and the development of new drugs targeting glutamate brain systems.     

New therapeutic strategy for mood disorders

The development of new treatments for mood disorders, as anxiety and depression, is based on identification of neural substrates and the mechanisms underlying their etiology and pathophysiology. The heterogeneity of mood disorders indicates that its origin may lie in dysfunction of multiple brain regions (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex). The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests the contribute of new neurons to the biology of mood disorders that is still under debate. The production of new neurons, referred to as neurogenesis, occurs throughout life in discrete brain areas such as the dentate gyrus (DG) of the hippocampus and the subventricular zone/olfactory bulb. Findings describing that neurogenesis process in DG is increased by antidepressants, like fluoxetine, and it is required for the behavioral effect of antidepressants, lead to a new strategy and drugs for the treatment of mood disorders. As many patients display poor response to therapy, research on depression and antidepressant drugs is necessary. In this regard, focusing on neurogenesis and neuroplasticity processes in experimental models is particularly interesting for the understanding of the pathophysiology of mood disorders and should define the role of adult-born neurons in hippocampal physiology. Different classes of drugs are currently prescribed for the treatment of mood disorders. Among them selective serotonin reuptake (SSRIs), monoamine oxidase inhibitors (MAOIs), specific norepinephrine reuptake inhibitors (SNRIs) and tricyclic acids (TCA) alleviate symptoms of mood disorders. Here we review different strategies that may be adopted for impairing mood disorders and that may be further developed for innovative therapeutic approaches.     

Phosphodiesterases in the CNS: targets for drug development

The therapeutic and commercial success of phosphodiesterase 5 inhibitors such as Viagra, Levitra and Cialis has sparked renewed interest in the phosphodiesterases as drug discovery targets. Virtually all the phosphodiesterases are expressed in the CNS, making this gene family a particularly attractive source of new targets for the treatment of psychiatric and neurodegenerative disorders. Significantly, all neurons express multiple phosphodiesterases, which differ in cyclic nucleotide specificity, affinity, regulatory control and subcellular compartmentalization. Therefore, phosphodiesterase inhibition represents a mechanism through which it could be possible to precisely modulate neuronal activity. In this article, we review the current state of the art in the burgeoning field of phosphodiesterase pharmacology in the CNS.     

Simulated apoptosis/neurogenesis regulates learning and memory capabilities of adaptive neural networks.

Characterization of neuronal death and neurogenesis in the adult brain of birds, humans, and other mammals raises the possibility that neuronal turnover represents a special form of neuroplasticity associated with stress responses, cognition, and the pathophysiology and treatment of psychiatric disorders. Multilayer neural network models capable of learning alphabetic character representations via incremental synaptic connection strength changes were used to assess additional learning and memory effects incurred by simulation of coordinated apoptotic and neurogenic events in the middle layer. Using a consistent incremental learning capability across all neurons and experimental conditions, increasing the number of middle layer neurons undergoing turnover increased network learning capacity for new information, and increased forgetting of old information. Simulations also showed that specific patterns of neural turnover based on individual neuronal connection characteristics, or the temporal-spatial pattern of neurons chosen for turnover during new learning impacts new learning performance. These simulations predict that apoptotic and neurogenic events could act together to produce specific learning and memory effects beyond those provided by ongoing mechanisms of connection plasticity in neuronal populations. Regulation of rates as well as patterns of neuronal turnover may serve an important function in tuning the informatic properties of plastic networks according to novel informational demands. Analogous regulation in the hippocampus may provide for adaptive cognitive and emotional responses to novel and stressful contexts, or operate suboptimally as a basis for psychiatric disorders. The implications of these elementary simulations for future biological and neural modeling research on apoptosis and neurogenesis are discussed.     

Constitutive activation of Galphas within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP.

Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas(*)) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Galphas(*) causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Galphas(*) increases cAMP levels in the striatum. Suprisingly, however, Galphas(*) mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Galphas(*) on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Galphas(*) mice and the cPDE inhibitor rolipram also rescues PPI deficits of Galphas(*) mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Galphas(*) mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Galphas(*). We conclude that expression of Galphas(*) within forebrain neurons causes PPI deficits because of a PKA-dependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.     

Histamine receptors in the CNS as targets for therapeutic intervention

Histamine has long been known to trigger allergic reactions and gastric acid secretion. However, it was later discovered that, in the brain, histamine regulates basic homeostatic and higher functions, including cognition, arousal, circadian and feeding rhythms. The sole source of brain histamine is neurons localized in the hypothalamic tuberomammillary nuclei. These neurons project axons to the whole brain, are organized into functionally distinct circuits influencing different brain regions and display selective control mechanisms. Although all histamine receptors (H1R, H2R, H3R and H4R) are expressed in the brain, only the H3R has become a drug target for the treatment of neurologic and psychiatric disorders, such as sleep disturbances and cognitive deficits. In this review, we discuss recent developments in the pharmacological manipulation of H3Rs and the implications for H3R-related therapies for neurological and psychiatric disorders. The legacy of Sir James Black.     

Chronic valproate normalizes behavior in mice overexpressing calcineurin

Calcineurin (PP2B) is a Ca(2+)-dependent protein phosphatase enriched in the brain that takes part in intracellular signaling pathways regulating synaptic plasticity and complex brain functions. We report here that when these pathways are activated by transgenic expression of calcineurin, locomotor activity of mice in response to novelty is increased, as well as the behavioral and molecular responses of the psychostimulant cocaine. We also observed that the anxious-like behavior is altered. These behavioral changes are indicative of a generally increased behavioral responsiveness and could be normalized by chronic treatment with the mood stabilizer valproate. These results provide proof of concept that calcineurin-dependent dephosphorylation plays an important role in behavioral reactivity and in the effects of mood regulators. Mice overexpressing calcineurin represent a novel tool to study affective responses related to psychiatric disorders.     

Epigenetics of psychoactive drugs

Objectives Epigenetics refers to the heritable, but reversible regulation of various biological functions. Changes in DNA methylation and chromatin structure derived from histone modifications are involved in the brain development, pathogenesis and pharmacotherapy of brain disorders. Key findings Evidence suggests that epigenetic modulations play key roles in psychiatric diseases such as schizophrenia and bipolar disorder. The analysis of epigenetic aberrations in the mechanisms of psychoactive drugs helps to determine dysfunctional genes and pathways in the brain, to predict side effects of drugs on human genome and identify new pharmaceutical targets for treatment of psychiatric diseases. Summary Although numerous studies have concentrated on epigenetics of psychosis, the epigenetic studies of antipsychotics are limited. Here we present epigenetic mechanisms of various psychoactive drugs and review the current literature on psychiatric epigenomics. Furthermore, we discuss various epigenetic modulations in the pharmacology and toxicology of typical and atypical antipsychotics, methionine, lithium and valproic acid.     

Infusing Neuroscience Into the Study and Prevention of Drug Misuse and Co-Occurring Aggressive Behavior

The etiology of behavioral precursors to substance misuse and aggression is viewed from the perspective of a developmental, multifactorial model of complex disorders. Beginning at conception, genetic and environmental interactions have potential to produce a sequence of behavioral phenotypes during development that bias the trajectory toward high-risk outcomes. One pathway is theorized to emanate from a deviation in neurological development that predisposes children to affective and cognitive delays or impairments that, in turn, generate dysregulatory behaviors. The plasticity of these neurobiological systems is highly relevant to the prevention sciences; their functions are reliant upon environmental inputs and can be altered, for better or for worse, contingent upon the nature of the inputs. Thus, social contextual factors confer significant influence on the development of this neural network and behavioral outcomes by increasing risk for, or protecting against, dysregulatory outcomes. A well-designed intervention can exploit the brain's plasticity by targeting biological and social factors at sensitive time points to positively influence emergent neurobiological functions and related behaviors. Accordingly, prevention research is beginning to focus on perturbations in developmental neural plasticity during childhood that increase the likelihood of risky behaviors and may also moderate intervention effects on behavior. Given that the more complex features of neurobiological functions underlying drug misuse and aggression (e.g., executive cognitive function, coping skills, affect regulation) do not coalesce until early adulthood when prefrontal-limbic brain networks consolidate, it is critical that mechanisms underlying developmental risk factors are identified. An empirically driven prevention approach, thus, may benefit from consideration of (i) the type, effect, and developmental timing of the environmental impact on the brain, and (ii) the type and effect on brain function, and developmental timing of the intervention. This translational approach promises to eventually offer some direction for the design of effective interventions to prevent drug misuse and concomitant aggression.     

Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization

Rationale Nicotine has been shown in a variety of studies in humans and experimental animals to improve cognitive function. Nicotinic treatments are being developed as therapeutic treatments for cognitive dysfunction. Objectives Critical for the development of nicotinic therapeutics is an understanding of the neurobehavioral bases for nicotinic involvement in cognitive function. Methods Specific and diverse cognitive functions affected by nicotinic treatments are reviewed, including attention, learning, and memory. The neural substrates for these behavioral actions involve the identification of the critical pharmacologic receptor targets, in particular brain locations, and how those incipient targets integrate with broader neural systems involved with cognitive function. Results Nicotine and nicotinic agonists can improve working memory function, learning, and attention. Both α4β2 and α7 nicotinic receptors appear to be critical for memory function. The hippocampus and the amygdala in particular have been found to be important for memory, with decreased nicotinic activity in these areas impairing memory. Nicotine and nicotinic analogs have shown promise for inducing cognitive improvement. Positive therapeutic effects have been seen in initial studies with a variety of cognitive dysfunctions, including Alzheimer's disease, age-associated memory impairment, schizophrenia, and attention deficit hyperactivity disorder. Conclusions Discovery of the behavioral, pharmacological, and anatomic specificity of nicotinic effects on learning, memory, and attention not only aids the understanding of nicotinic involvement in the basis of cognitive function, but also helps in the development of novel nicotinic treatments for cognitive dysfunction. Nicotinic treatments directed at specific receptor subtypes and nicotinic cotreatments with drugs affecting interacting transmitter systems may provide cognitive benefits most relevant to different syndromes of cognitive impairment such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder. Further research is necessary in order to determine the efficacy and safety of nicotinic treatments of these cognitive disorders.