Cellular neurobiology of hyperforin.

Hyperforin is a phloroglucinol derivative isolated from the medicinal plant Hypericum perforatum (St John's wort, SJW). This lipophilic biomolecule displays antibacterial, pro-apoptotic, antiproliferative, and anti-inflammatory activities. In addition, in vitro and in vivo data showed that hyperforin is a promising molecule with potential applications in neurology and psychiatry. For instance, hyperforin possesses antidepressant properties, impairs the uptake of neurotransmitters, and stimulates the brain derived neurotrophic factor (BDNF)/TrkB neurotrophic signaling pathway, the adult hippocampal neurogenesis, and the brain homeostasis of zinc. In fact, hyperforin is a multi-target biomolecule with a complex neuropharmacological profile. However, one prominent pharmacological feature of hyperforin is its ability to influence the homeostasis of cations such as Ca2+ , Na+ , Zn2+ , and H+ . So far, the pathophysiological relevance of these actions is currently unknown. The main objective of the present work is to provide an overview of the cellular neurobiology of hyperforin, with a special focus on its effects on neuronal membranes and the movement of cations.

Polyphenols in Inner Ear Neurobiology, Health and Disease: From Bench to Clinics.

There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose-response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose-response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose-response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.

A comparative multi-level toxicity assessment of carbon-based Gd-free dots and Gd-doped nanohybrids from coffee waste: hematology, biochemistry, histopathology and neurobiology study.

Here, a comparative toxicity assessment of precursor carbon dots from coffee waste (cofCDs) obtained using green chemistry principles and Gd-doped nanohybrids (cofNHs) was performed using hematological, biochemical, histopathological assays in vivo (CD1 mice, intraperitoneal administration, 14 days), and neurochemical approach in vitro (rat cortex nerve terminals, synaptosomes). Serum biochemistry data revealed similar changes in cofCDs and cofNHs-treated groups, i.e. no changes in liver enzymes' activities and creatinine, but decreased urea and total protein values. Hematology data demonstrated increased lymphocytes and concomitantly decreased granulocytes in both groups, which could evidence inflammatory processes in the organism and was confirmed by liver histopathology; decreased red blood cell-associated parameters and platelet count, and increased mean platelet volume, which might indicate concerns with platelet maturation and was confirmed by spleen histopathology. So, relative safety of both cofCDs and cofNHs for kidney, liver and spleen was shown, whereas there were concerns about platelet maturation and erythropoiesis. In acute neurotoxicity study, cofCDs and cofNHs (0.01 mg/ml) did not affect the extracellular level of L-[14C]glutamate and [3H]GABA in nerve terminal preparations. Therefore, cofNHs demonstrated minimal changes in serum biochemistry and hematology assays, had no acute neurotoxicity signs, and can be considered as perspective biocompatible non-toxic theragnostic agent.

Initial evidence regarding the neurobiological basis of psychological symptoms in dementia caregivers.

Mood symptoms and disorders are common in dementia caregivers, who can be exposed to a myriad of potential stressors including their care recipient's neuropsychiatric symptoms. Existing evidence indicates that the effects of potentially stressful exposures on mental health depend on the caregiver's individual characteristics and responses. Specifically, prior studies indicate that risk factors measured on psychological (e.g., emotion-focused/behaviorally disengaged coping responses) and behavioral (e.g., sleep and activity restriction) levels of analysis may confer the effects of caregiving exposures on mental health. Theoretically, this process from caregiving stressors and other risk factors to mood symptoms is neurobiologically mediated. This article reviews recent studies that used brain imaging to identify neurobiological factors that are related to psychological outcomes in caregivers. Available observational data indicate that psychological outcomes in caregivers are related to differences in the structure/function of regions involved in socio-affective information processing (prefrontal), autobiographical memory (the posterior cingulate), and stress (amygdala). In addition, two small randomized controlled trials using repeated brain imaging showed that Mentalizing Imagery Therapy (a mindfulness program) increased prefrontal network connectivity and reduced mood symptoms. These studies raise the possibility that, in the future, brain imaging may be useful to detect the neurobiological basis of a given caregiver's mood vulnerability and guide the selection of interventions that are known to modify it. However, there remains a need for evidence on whether brain imaging improves on simpler/inexpensive measurement modalities like self-report for identifying vulnerable caregivers and matching them with efficacious interventions. In addition, to target interventions, more evidence is needed regarding the effects that both risk factors and interventions have on mood neurobiology (e.g., how persistent emotion-focused coping, sleep disruption, and mindfulness affect brain function).

How to save a life: From neurobiological underpinnings to psychopharmacotherapies in the prevention of suicide.

The impact of suicide on our societies, mental healthcare, and public health is beyond questionable. Every year approximately 700 000 lives are lost due to suicide around the world (WHO, 2021); more people die by suicide than by homicide and war. Although suicide is a key issue and reducing suicide mortality is a global imperative, suicide is a highly complex biopsychosocial phenomenon, and in spite of several suicidal models developed in recent years and a high number of suicide risk factors identified, we still have neither a sufficient understanding of underpinnings of suicide nor adequate management strategies to reduce its prevalence. The present paper first overviews the background of suicidal behavior including its epidemiology, age and gender correlations, and its association with neuropsychiatric disorders as well as its clinical assessment. Then we give an overview of the etiological background, including its biopsychosocial contexts, genetics and neurobiology. Based on the above, we then provide a critical overview of the currently available intervention options to manage and reduce risk of suicide, including psychotherapeutic modalities, traditional medication classes also providing an up-to-date overview on the antisuicidal effects of lithium, as well as novel molecules such as esketamine and emerging medications and further molecules in development. Finally we give a critical overview on our current knowledge on using neuromodulatory and biological therapies, such as ECT, rTMS, tDCS, and other options.

Behavioural disruption in diabetic mice: Neurobiological correlates and influences of dietary α-linolenic acid.

AIM: Evolving type 2 diabetes (T2D) may influence locomotion and affective state, promoting metabolic dysfunction. We examined behaviour and neurobiology in a model of T2D, testing for benefits with dietary n-3 polyunsaturated fatty acid (PUFA). METHODS: Male C57Bl/6 mice received vehicle or 75 mg/kg streptozotocin (STZ) and 21 wks of control or Western diets (43 % fat, 40 % carbohydrate, 17 % protein). Sub-sets received dietary α-linolenic acid (ALA; 10 % of fat intake) for 6 wks. Behaviour was examined via open field and sucrose preference tests, and hippocampal and frontal cortex (FC) leptin and dopamine levels and inflammatory signalling assessed. KEY FINDINGS: T2D mice exhibited weight gain (+15 %), hyperglycemia (+35 %), hyperinsulinemia (+60 %) and insulin-resistance (+80 % higher HOMA-IR), together with anxiety-like behaviour (without anhedonia) that appeared independent of body weight and glycemic status. Cortical leptin declined whereas receptor mRNA increased. Supplementation with ALA did not influence metabolic state, while enhancing locomotion and reducing anxiety-like behaviours in healthy but not T2D mice. Hippocampal dopamine was selectively increased by ALA in T2D mice, with a trend to reduced circulating leptin in both groups. Across all groups, anxiety-like behaviour was associated with declining cortical and hippocampal leptin levels and increasing receptor mRNA, while declining dopamine levels were accompanied by decreased dopamine/serotonin receptor transcripts. SIGNIFICANCE: Chronic T2D induced anxiogenesis in mice appears to be independent of metabolic homeostasis but linked to central leptin-resistance, together with disturbed dopamine and serotonin signalling. Despite anxiolytic effects of ALA in healthy mice, no metabolic or behavioural benefits were evident in T2D.

A voice without a mouth no more: The neurobiology of language and consciousness.

Most research on the neurobiology of language ignores consciousness and vice versa. Here, language, with an emphasis on inner speech, is hypothesised to generate and sustain self-awareness, i.e., higher-order consciousness. Converging evidence supporting this hypothesis is reviewed. To account for these findings, a 'HOLISTIC' model of neurobiology of language, inner speech, and consciousness is proposed. It involves a 'core' set of inner speech production regions that initiate the experience of feeling and hearing words. These take on affective qualities, deriving from activation of associated sensory, motor, and emotional representations, involving a largely unconscious dynamic 'periphery', distributed throughout the whole brain. Responding to those words forms the basis for sustained network activity, involving 'default mode' activation and prefrontal and thalamic/brainstem selection of contextually relevant responses. Evidence for the model is reviewed, supporting neuroimaging meta-analyses conducted, and comparisons with other theories of consciousness made. The HOLISTIC model constitutes a more parsimonious and complete account of the 'neural correlates of consciousness' that has implications for a mechanistic account of mental health and wellbeing.

A Systems Approach to Behavioral Neurobiology: Integrating Psychodynamics and Neuroscience in a Psychiatric Curriculum.

In the practice of medicine, an understanding of the biological functioning of organs and organ systems is the basis for theories of pathology and clinical practice. If psychoanalysis is to be accepted by the medical and psychiatric community, it must be based on a sophisticated understanding of the organ from which mental and emotional experiences emanate and use scientifically acceptable language. Each approach to psychotherapy has its own vocabulary for describing neuropsychological processes. Neurobiological vocabulary provides the various factions "neutral ground" upon which to carry on a multidisciplinary integrative dialogue. An understanding of behavioral neuroscience allows the therapist to look beyond the labels that spawn division and identify unifying biological principles that are described in a variety of ways in a multitude of theories. We contend that the neural network/representational approach to neurobiology views human mental experience as the result of multiple complex integrated systems, and is therefore holistic and antireductionistic in its perspective. Such a biologically informed psychotherapy facilitates integration of skill sets and flexibility in technique. With these principles in mind, the therapist can base his or her approach to the patient based on these principles rather than on devotion to one particular "school" or another. Because behavioral neuroscience supports many of the basic tenets of psychoanalytic theory, such an integrative psychotherapy would be psychody-namically informed. In this paper, we outline some of the ideas we present in our neuroscience course and how we relate biological concepts with some core principles of psychodynamics and psychotherapy.

Clinical Approaches to Cannabis: A Narrative Review.

Cannabis use in the United States is growing at an unprecedented pace. Most states in the United States have legalized medical cannabis use, and many have legalized nonmedical cannabis use. In this setting, health care professionals will increasingly see more patients who have questions about cannabis use, its utility for medical conditions, and the risks of its use. This narrative review provides an overview of the background, pharmacology, therapeutic use, and potential complications of cannabis.

Massage and touch-based therapy : Clinical evidence, neurobiology and applications in older patients with psychiatric symptoms.

BACKGROUND: Massage and touch-based treatment are popular despite limited evidence from high quality clinical trials. This article reviews the rationale and evidence of treating older patients with psychiatric symptoms by touch-based therapy. METHODS: Narrative literature review, based on Medline search with the following key words: massage, social touch, affective touch, clinical trial, meta-analysis. Citations of identified articles were searched for additional relevant studies. RESULTS: Evidence from clinical trials in adult patients with mainly chronic disorders of the musculoskeletal system suggests that massage therapy results in significant short-term improvement of symptoms; however, treatment effects appear not to be sustained. In addition, conclusions are difficult to draw owing to very heterogeneous study interventions, difficulties with definition of control conditions and treatment outcomes. There appears to be better evidence for improvement of psychological variables and subjective symptoms, such as pain and quality of life. A neuronal system of affective and social touch has been identified with specific afferents from C­fibre coupled low threshold mechanoreceptors projecting into the insular cortex and the limbic system. This system may also mediate effects of massage in adult patients. Positive clinical trials for depressive symptoms of dementia and for behavioral symptoms of advanced dementia are available with encouraging results. CONCLUSION: The neuronal system of social and affective touch suggests a potential mechanism of action of touch-based interventions in geriatric psychiatry. In addition, it provides a rationale for applying and designing novel touch-based treatment strategies as adjunctive treatment for psychiatric disorders of old age.

Neurobiology of puberty and its disorders.

Puberty, which in humans is considered to include both gonadarche and adrenarche, is the period of becoming capable of reproducing sexually and is recognized by maturation of the gonads and development of secondary sex characteristics. Gonadarche referring to growth and maturation of the gonads is fundamental to puberty since it encompasses increased gonadal steroid secretion and initiation of gametogenesis resulting from enhanced pituitary gonadotropin secretion, triggered in turn by robust pulsatile GnRH release from the hypothalamus. This chapter reviews the development of GnRH pulsatility from before birth until the onset of puberty. In humans, GnRH pulse generation is restrained during childhood and juvenile development. This prepubertal hiatus in hypothalamic activity is considered to result from a neurobiological brake imposed upon the GnRH pulse generator resident in the infundibular nucleus. Reactivation of the GnRH pulse generator initiates pubertal development. Current understanding of the genetics and physiology of the brake will be discussed, as will hypotheses proposed to account for timing the resurgence in pulsatile GnRH and initiation of puberty. The chapter ends with a discussion of disorders associated with precocious or delayed puberty with a focus on those with etiologies attributed to aberrant GnRH neuron anatomy or function. A pediatric approach to patients with pubertal disorders is provided and contemporary treatments for both precocious and delayed puberty outlined.

The neurobiology of abstinence-induced reward-seeking in males and females.

Drugs of abuse and highly palatable foods (e.g. high fat or sweet foods) have powerful reinforcing effects, which can lead to compulsive and addictive drives to ingest these substances to the point of psychopathology and self-harm--specifically the development of Substance Use Disorder (SUD) and obesity. Both SUD and binge-like overeating can be defined as disorders in which the salience of the reward (food or drug) becomes exaggerated relative to, and at the expense of, other rewards that promote well-being. A major roadblock in the treatment of these disorders is high rates of relapse after periods of abstinence. It is common, although not universal, for cue-induced craving to increase over time with abstinence, often triggered by cues previously paired with the reinforcing substance. Accumulating evidence suggests that similar neural circuits and cellular mechanisms contribute to abstinence-induced and cue-triggered seeking of drugs and palatable food. Although much research has focused on the important role of corticolimbic circuitry in drug-seeking, our goal is to expand focus to the more recently explored hypothalamic-thalamic-striatal circuitry. Specifically, we review how connections, and neurotransmitters therein, among the lateral hypothalamus, paraventricular nucleus of the thalamus, and the nucleus accumbens contribute to abstinence-induced opioid- and (high fat or sweet) food-seeking. Given that biological sex and gonadal hormones have been implicated in addictive behavior across species, another layer to this review is to compare behaviors and neural circuit-based mechanisms of abstinence-induced opioid- or food-seeking between males and females when such data is available.

Reflections on Bruce S. McEwen's contributions to stress neurobiology and so much more.

The authors highlight, from a firsthand perspective, Bruce S. McEwen's seminal influence on the field of stress neurobiology and beyond, and how these investigations have yielded important insights, principles and critical questions that continue to guide stress research today. Featured are discussion of: 1) the important inverted-U relationship between stress/glucocorticoids and optimal physiological function, 2) stress adaptation and the role of adaptive stress responses, 3) mechanisms by which the short-term stress response promotes heightened immune function and immunity, and 4) the far reaching impact of the theoretical framework of allostasis and allostatic load-concepts that have created new bridges between stress physiology, biomedical sciences, health psychology and sociology.

[Self-healing in health-care: Using the example of mind-body medicine]. / Der Nutzen von Selbstheilungspotenzialen in der professionellen Gesundheitsfürsorge am Beispiel der Mind-Body-Medizin.

Mind-body medicine (MBM) is based on the assumption that interactions between the brain, mind, body, and behavior can be used to activate health-promoting pathways towards better health. It includes behavioral medical approaches and techniques in conjunction with exercise, relaxation, stress regulation, and nutrition. MBM and MBM interventions are well-established in the US healthcare system. This also includes an exploration of their underlying mechanisms. In Germany, too, a growing body of interventions are now summarized under this generic term.In this narrative review, the emergence of MBM is illuminated in the context of historical developments as well as against the background of the meditation research that has been emerging since the 1970s and the investigation of the stress phenomenon. References to basic research including neurobiological reward/placebo physiology are presented. Distinctions to psychotherapy are made and an implementation framework is described.MBM is related to health promotion and the therapy of chronic, especially lifestyle-related diseases. It is based on the salutogenesis approach, i.e., a paradigm that seeks to explore and reinforce health determinants and resistance resources (individual resilience and coherence factors) and strives to reduce stress. This approach corresponds to self-healing or self-care principles. Neurobiologically, it is associated with the placebo effect. MBM interventions typically follow the BERN model (behavior-exercise-relaxation-nutrition).As a facilitator of self-healing and self-care, MBM can be professionally trained and empowered. For doing so, "health promotion experts" are used.

Healing Intergenerational Wounds: An Integrative Relational-Neurobiological Approach.

Old resentments and unfinished business from the family of origin can constrain adults in current relationships with parents or siblings and negatively affect relationships with partners or children. This article explores how old wounds get reactivated in current relationships and contribute to the intergenerational transmission of painful legacies and trauma. Building on intergenerational family theory and interpersonal neurobiology, the dynamics of reactivity and pathways for growth are explored. While much of the time the human brain is on autopilot, driven by habits and emotional reactivity, we are capable of bringing prefrontal thoughtfulness and choice to close relationships. Rather than being victims of parents or our past, we can become authors of our own relational life. Interventions are offered to help adult clients "wake from the spell of childhood," heal intergenerational wounds, and "grow up" relationships with family of origin. The damage caused by parent-blaming in therapy is explored and contrasted with Ivan Boszormenyi-Nagy's emphasis on rejunctive action and cultivating resources of trustworthiness in intergenerational relationships. The family is considered both in its cultural context-including stressors and resources for resilience-and in its life cycle context. Aging in the intergenerational family is discussed, focusing on ways adult children and their parents can grow and flourish with the challenges at this time of life. Throughout, the theme of relational ethics-how we can live according to our values and "reach for our best self" in intergenerational relationships-informs the discussion.

Los viejos resentimientos y las cuentas pendientes de la familia de origen pueden limitar a los adultos en sus relaciones actuales con sus padres o hermanos y afectar negativamente las relaciones con la pareja o los hijos. Este artículo analiza cómo las antiguas heridas se reactivan en las relaciones actuales y contribuyen a la transmisión intergeneracional de legados dolorosos y traumas. Sobre la base de la teoría familiar intergeneracional y la neurobiología interpersonal, se analizan la dinámica de la reactividad y las vías de crecimiento. Si bien gran parte del tiempo el cerebro humano está en piloto automático, impulsado por los hábitos y la reactividad emocional, somos capaces de llevar atención y elección prefrontal a las relaciones estrechas. En lugar de ser víctimas de los padres o de nuestro pasado, podemos convertirnos en autores de nuestra propia vida relacional. Se ofrecen intervenciones para ayudar a pacientes adultos a "despertar del hechizo de la infancia", a curar heridas intergeneracionales y a "madurar" las relaciones con la familia de origen. Se estudia el daño causado por culpar a los padres en terapia y se compara con el énfasis de Ivan Boszormeny-Nagy en la acción redentora y en el cultivo de los recursos de la confianza en las relaciones intergeneracionales. Se tiene en cuenta a la familia tanto en su contexto cultural-incluidos los factores desencadenantes de estrés y los recursos para la resiliencia-como en su contexto de ciclo de vida. Se debate el envejecimiento en la familia intergeneracional centrándose en las maneras en las que los hijos adultos y sus padres pueden crecer y prosperar con las dificultades en este momento de la vida. Desde el principio hasta el final, el tema de la ética relacional-cómo podemos vivir de acuerdo con nuestros valores y "alcanzar nuestro mejor yo" en las relaciones intergeneracionales-respalda del debate.

Current Understanding of Religion, Spirituality, and Their Neurobiological Correlates.

Religion and spirituality (R/S) have been prominent aspects of most human cultures through the ages; however, scientific inquiry into this phenomenon has been limited. We conducted a systematic literature review of research on the neurobiological correlates of R/S, which resulted in 25 reports studying primarily R/S with electroencephalography, structural neuroimaging (MRI), and functional neuroimaging (fMRI, PET). These studies investigated a wide range of religions (e.g., Christianity, Buddhism, Islam) and R/S states and behaviors (e.g., resting state, prayer, judgments) and employed a wide range of methodologies, some of which (e.g., no control group, varying measures of religiosity, small sample sizes) raise concerns about the validity of the results. Despite these limitations, the findings of these studies collectively suggest that the experience of R/S has specific neurobiological correlates and that these correlates are distinct from non-R/S counterparts. The findings implicate several brain regions potentially associated with R/S development and behavior, including the medial frontal cortex, orbitofrontal cortex, precuneus, posterior cingulate cortex, default mode network, and caudate. This research may suggest future clinical applications and interventions related to R/S and various disorders, including mood, anxiety, psychotic, pain, and vertiginous disorders. Further studies with more rigorous study designs are warranted to elucidate the neurobiological mechanisms of R/S and their potential clinical applications.

Iron, Myelin, and the Brain: Neuroimaging Meets Neurobiology.

Although iron is crucial for neuronal functioning, many aspects of cerebral iron biology await clarification. The ability to quantify specific iron forms in the living brain would open new avenues for diagnosis, therapeutic monitoring, and understanding pathogenesis of diseases. A modality that allows assessment of brain tissue composition in vivo, in particular of iron deposits or myelin content on a submillimeter spatial scale, is magnetic resonance imaging (MRI). Multimodal strategies combining MRI with complementary analytical techniques ex vivo have emerged, which may lead to improved specificity. Interdisciplinary collaborations will be key to advance beyond simple correlative analyses in the biological interpretation of MRI data and to gain deeper insights into key factors leading to iron accumulation and/or redistribution associated with neurodegeneration.

Neurobiology of Trauma and Mindfulness for Children.

Adverse child experiences (ACEs) have a significant impact on developing children, both physically and psychologically, with ongoing consequences that may manifest throughout adulthood. These negative health consequences can be mitigated if a child is given a supportive environment in which to develop healthy coping mechanisms. Those who specialize in caring for children with ACEs must understand the neurobiology of trauma to conceptualize how trauma triggers the brain and body when encountering stressful events. Mindfulness is an evidence-based practice that can be used as a healthy coping mechanism to develop self-regulation and resiliency in children. The purpose of this article is to provide evidenced-based research on the neurobiology of trauma and mindfulness intervention as a recommended modality for use in children. Furthermore, the content in this article was utilized in developing a training module for a suburban, youth organization that provides residential housing, basic necessities, education, and therapy for children with ACEs. The training module is intended to assist staff members in understanding the neurobiology of trauma and mindfulness techniques in their interactions with the children, thereby improving child-staff relationships and encouraging the development of self-regulation and healthy coping mechanisms.