The nucleus accumbens (NAc), the ventral part of the striatum, plays a critical role in motivation, learning, and cognition in the basal ganglia circuit. Outputs of the NAc are transmitted through two parallel direct and indirect pathways. We have developed a reversible neurotransmission blocking (RNB) technique, in which neurotransmission of each pathway in the NAc is selectively blocked by specific expression of a transmission-blocking tetanus toxin (D-RNB or I-RNB). In visual cue and reversal tasks in the cross-maze, the NAc direct pathway was critical for learning acquisition. In contrast, the NAc indirect pathway was essential not only for learning flexibility, but also for subsequent acquisition of a new strategy. In place discrimination and serial reversal learning tasks in the IntelliCage, we showed that the NAc indirect pathway controls behavioral flexibility by suppressing the influence of previously correct behavioral strategies during the reversal stage. These basal ganglia circuit mechanisms provide new insight into pathophysiologies associated with compulsive behaviors, including addiction and obesity.
Visual cortical neurons selectively respond to particular features of visual stimuli. Selective visual responsiveness is modified by visual expe- rience during development. We report that fine-scale networks of precisely interconnected excitatory neurons were embedded in the rat visual cortex and suggest that this network could be a functional unit for visual information processing. We also investigated the effects of visual dep- rivation on the development of visual cortical circuits. We used two kinds of deprivation, binocular deprivation and dark rearipg, which allowed visual inputs with only diffuse light and no visual input, respectively. The probability and strength of excitatory connections t layer 2/3 pyrami- dal cells increased during the 2 weeks after eye opening, and these changes were prevented by dark rearing, but not binocular eprivation. Fine- scale networks were absent just after eye opening and established during the following 2 weeks in rats reared with normal visual experience, but not with either type of deprivation. These results indicate that patterned vision is required for the emergence of the fine-scale network, whereas diffuse light stimulation is sufficient for the mituration of individual synapses. The critical role of early sensory experience may be to organize cell assemblies underlying visual information processing in the visual cortex.
The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca2+-activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors.
Psychiatric disorders such as schizophrenia and depression are considered to be complex diseases that result from an interaction of many ge- netic and environmental risk factors associated with the diseases. The underlying molecular mechanisms, however, remain largely unknown and there are conditions, the treatment of which is not necessarily satisfactory due to inadequate therapeutic effect or treatment resistance. Therefore, scientific research on the brain functions and dysfunctions as well as development of better treatments is crucially important. In the present review, I will attempt to discuss such a research using animal disease models together with genetic studies in human disorders and point out future directions of the translational research on psychiatric disorders.
The positive outcome that hypothermia contributes to brain and cardiac protection following ischemia has stimulated research in the development of pharmacological approaches to induce a hypothermic/hypometabolic state. Pharmacological manipulation of central autonomic thermoregulatory circuits could represent a potential target for the induction of a hypothermic state. Here we present a brief description of the CNS thermoregulatory centers and how the manipulation of these circuits can be useful in the treatment of pathological conditions such as stroke or brain hemorrhage.
The current nomenclature is based on clinical indications; for example, drugs used for mania and psychosis are classified as "mood stabilizers" and "antipsychotic drugs", respectively. This discrepancy between their names and indications often confuses patients and their caregivers and sometimes leads to a misunderstanding of the effects of prescribed medications. In addition, up-to-date scientific knowledge on these drugs has not been reflected in the current nomenclature. To overcome these limitations of the current nomenclature, following an initiative of the European Congress of Neuropsychopharmacology (ECNP), a taskforce for psychotropic nomenclature was established with representatives from 5 international organizations, including the Asian College of Neuropsychopharmacology (AsCNP). The mission of this taskforce is to provide a pharmacologically-driven (rather than indication-based) nomenclature, which is now referred to as Neuroscience-based Nomenclature (NbN). The NbN project has just started. Since it always takes time to change the culture, we understand the transition will likely involve some expected and unexpected responses from the field. However, we believe that such responses and feedback will surely improve the quality of the NbN, which in turn will be beneficial for clinicians, researchers, and patients as well as their caregivers.
Family, twin and adoption studies have revealed genetic factors involved in suicide, while the accumulation of stress and mental illnesses are major contributing factors of suicide. Since higher lethality of suicidal behavior is considered to increase familial liability to suicidal behavior, we believe biological research of completed suicide is most important for a better understanding of the pathophysiology in suicide. Dysregulated hypothalamic-pituitary-adrenal axis has gained a special interest in the neurobiology of suicide, mostly because of the findings using a dexamethasone suppression test (DST), in which DST non-suppressors show a nearly 10-fold higher risk of completed suicide than DST suppressors in a depressed cohort. Other data mainly from postmortem brain studies indicate abnormalities of the noradrenergic-locus coeruleus system, serotonergic system, endogenous opioid system, brain-derived neurotrophic factor, inflammatory cytokines and omega-3 fatty acid in completed suicide. However, genetic research of complete suicide is behind other mental problems because it is extremely difficult to obtain tissue samples of completed suicide. Under the difficult situation, we now retain over 800 blood samples of suicide completers thanks to bereaved families' cooperation. We are actively working on the research of suicide, for instance, by performing a GWAS using 500 samples of suicide completers.
Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre-study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady-state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 μg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues.
Capsaicin receptor TRPV1 and wasabi receptor TRPA1 are expressed in the unmyelinated C fiber nociceptors and activated by various nociceptive stimuli causing pain in our body. Their involvement in nociception was proven with behavior studies using mice lacking TRPV1 and TRPA1. TRPV1 was found to interact with a calcium-activated chloride channel, anoctamin1 (ANO1), and calcium ions entering the primary sensory neurons activated ANO1, leading to chloride efflux which resulted in further depolarization. This is a novel pain-enhancing mechanism. A splicing variant of mouse TRPA1 (TRPA1b) was identified, and TRPA1b was found to bind to the full length TRPA1 (TRPA1a) and enhance the translocation of TRPA1a to the plasma membrane, leading to the increase in TRPA1 activity. The increase in TRPA1b transcript in the inflammatory and neuropathic pain conditions suggests the involvement of TRPA1b in the increased pain sensation under pathological conditions. Regulation of TRPV1/ANO1 complex formation or TRPA1b production could be a promising way to develop novel analgesic agents.
Cell positioning and neuronal network formation are crucial for proper brain function. Disrupted-In-Schizophrenia 1 (DISC1) is anterogradely transported to the neurite tips, together with Lis1, and functions in neurite extension via suppression of GSK3β activity. Then, transported Lis1 is retrogradely transported and functions in cell migration. Here, we show that DISC1-binding zinc finger protein (DBZ) regulates mouse cortical cell positioning and neurite development in vivo, together with DISC1. DBZ hindered Ndel1 phosphorylation at threonine 219 and serine 251. DBZ depletion or expression of a double-phosphorylated mimetic form of Ndel1 impaired the transport of Lis1 and DISC1 to the neurite tips and hampered microtubule elongation. Moreover, application of DISC1 or a GSK3β inhibitor rescued the impairments caused by DBZ insufficiency or double-phosphorylated Ndel1 expression. We concluded that DBZ controls cell positioning and neurite development by interfering with Ndel1 from disproportionate phosphorylation, which is critical for appropriate anterograde transport of the DISC1-complex.
Oxidative stress and neuroinflammation have recently been focused on the pathological hypotheses of schizophrenia. N-acetylcysteine (NAC) is a precursor of endogenous antioxidant glutathione and has antioxidant, anti-inflammatory, and neuroprotective properties. NAC is widely available as an over-the-counter nutritional supplement. Increasing lines of evidence suggest that NAC is effective for various mental disorders. In randomized controlled trials, treatment with NAC as an add-on to antipsychotics showed beneficial effects and safety profiles in patients with chronic schizophrenia. The results of a recent preclinical study using a neurodevelopmental model of schizophrenia suggest that NAC may have promising effects in an early stage of schizophrenia and an at-risk mental state. However, there is little clinical evidence for the efficacy and safety of NAC at these stages of schizophrenia. In this review, we summarize the evidence regarding the effectiveness of NAC for the treatment of schizophrenia and its prodromal stage. We also introduce the preliminary results of our research on NAC.
The concept of intermediate phenotype was proposed by Dr. Weinberger of the National Institute of Mental Health (NIMH). The risk genes for mental disorders define intermediate phenotypes, neurobiological characteristics observed in psychiatric disorders, and intermediate phenotypes increase the risk of mental disorders. The author worked at Dr. Weinberger's laboratory, and after returning home, introduced the concept to Japan, creating a term "Chukanhyogengata" to translate "intermediate phenotype". Intermediate phenotype has been proposed as a tool for the identification of risk genes for mental disorders, spreading the concept as a biomarker for the bridging between genes and behaviors. Intermediate phenotype studies later became one of the main pillars of psychiatric research. As a large number of data and samples are needed for intermediate phenotype research, we built a research resource database that combines the brain phenotype and bioresources. We performed genome-wide association analysis of cognitive decline in schizophrenia and identified the DEGS2 gene using this sample. This research resource database was developed for a multicenter study by COCORO (Cognitive Genetics Collaborative Research Organization). COCORO carried out genome-wide association analysis of the gray matter volume of the superior temporal gyrus and identified genome-wide significant loci. In this paper, we introduce the concept and history of intermediate phenotype study of mental illness and the latest trends. We hope to contribute to the future development of mental illness research through translational research.
Recent advances in neuroimaging studies enable us to measure brain function non-invasively. Over the past several decades, neuroimaging measurement has been substantially applied to elucidate the neurobiological mechanisms underlying major depressive disorder (MDD). Since MDD is a wide spectrum which consists of various symptoms such as low mood or loss of interest and is considered to affect a biologically het- erogeneous population, we have not yet elucidated the biological underpinnings of MDD. It seems to be more promising to consider MDD as an integral network abnormality instead of deficits in specific brain regions or neurotransmitters. We firstly provide a comprehensive review of the extant neuroimaging literature including structural and functional magnetic resonance imaging, magnetic resonance spectroscopy, single pho- ton emission computed tomography, and positron emission tomography studies. Then we show our neuroimaging studies for MDD toward po- tential application as a biomarker for diagnosis and treatment. We believe it will facilitate the development, of a more integrative model of neural dysfunction in MDD.
Optogenetics is a recently developed experimental technique to control the activity of neurons using light. Optogenetics shows its power to reveal the physiological role of specific neural circuits in the brain. In particular, manipulation of a specific type of neurons using optogenetics with high accuracy timing enables us to analyze causality between neural activity and initiation of animal behaviors. However, to manipulate the activity of specific neurons in vivo, there are two critical steps to succeed in manipulation of the neural activity and control of the behavior of individual animals. The first step is an adequate number of molecules of light-activated protein that has to be expressed in the cell membrane of the neurons of interest. The second step is the optical system to illuminate the targeted neurons with enough intensity of light to activate the light-activated protein. We applied optogenetics to hypothalamic peptidergic neurons such as orexin/hypocretin neurons or melanin concentrating hormone (MCH) neurons. These neurons are implicated in sleep/wakefulness regulation. In this mini review, I will show the regulatory mechanism of sleep/wakefulness by these neurons using optogenetics.
Organisms living outside of tropical zones experience seasonal changes in environment. Organisms are using day length as a calendar to change their physiology and behavior such as seasonal breeding, hibernation, migration, and molting. A comparative biology approach revealed underlying mechanisms of vertebrate seasonal reproduction. Here we review the current understanding of vertebrate seasonal reproduction. We Aso describe the involvement of tissue-specific post-translational modification in functional diversification of a hormone.
Organisms living outside of tropical zones experience seasonal changes in environment. Organisms are using day length as a calendar to change their physiology and behavior such as seasonal breeding, hibernation, migration, and molting. A comparative biology approach revealed underlying mechanisms of vertebrate seasonal reproduction. Here we review the current understanding of vertebrate seasonal reproduction. We also describe the involvement of tissue-specific post-translational modification in functional diversification of a hormone.
Genetic factors are involved in determinants for the risk of psychiatric disorders, and neurological and neurodegenerative diseases. Chronic pain stimuli and intense pain have effects at a cellular and/or gene expression level, and will eventually induce "cellular memory due to pain", which means that tissue damage, even if only transient, can elicit epigenetically abnormal transcription/translation and post-translational modification in related cells depending on the degree or kind of injury or associated conditions. Such cell memory/transformation due to pain can cause an abnormality in a fundamental intracellular response, such as a change in the three-dimensional structure of DNA, transcription, or translation. On the other hand, pain is a multidimensional experience with sensory-discriminative and motivational-affective components. Recent human brain imaging studies have examined differences in activity in the nucleus accumbens between controls and patients with chronic pain, and have revealed that the nucleus accumbens plays a role in predicting the value of a noxious stimulus and its offset, and in the consequent changes in the motivational state. In this review, we provide a very brief overview of a comprehensive understanding of chronic pain associated with emotional dysregulation due to transcriptional regulation, epigenetic modification and miRNA regulation.
Glial cells receive neurotransmitters, respond to them, and then release so-called gliotransmitters such as ATP, glutamate or D-serine. Astrocytes in particular have received much attention because synaptic structures are surrounded by astrocytic fine processes, by which astrocytes communicate with neurons via gliotransmitters. Here, we introduce recent progress concerning glia-neuron interaction, especially focusing on the major gliotransmitter ATP and astrocytes in parallel with the latest progress in glia-imaging techniques.
