The post-therapeutic effect of rapamycin in mild traumatic brain-injured rats ensuing in the upregulation of autophagy and mitophagy.

Mild traumatic brain injury (mTBI), common in juveniles, has been reported to be caused by sports-related concussion. Many young children may suffer from post-concussion syndrome. mTBI, in early stages of life, could play a part in neuron apoptosis and degeneration, cognitive and motor coordination impairment, as well as dementia. Our study was aimed at further investigating the post-therapeutic efficacy of rapamycin in the recuperation of mTBI while at the same time investigating the metamorphosis in both autophagy and mitophagy in mTBI. We created a weight-drop rat mTBI model with the administration of rapamycin at 4 h after every mTBI. Behavioral tests of beam walking and open field task indicated the expected improvement of cognitive and motor coordination functions. Both Western blot and immunofluorescence examinations revealed increased Beclin-1 and PINK1 in the treated rats as well as reduction of caspase-3 and cytochrome C (Cyt C). More so, the TUNEL staining evidenced curtailment of apoptotic cells following treatment with rapamycin. The upregulation of Beclin-1 and PINK1 and the downregulation of caspase-3 and Cyt C extrapolate that rapamycin plays neuroprotective as well as anti-apoptotic role via interposition of both autophagy and mitophagy.

GLP-1 derivatives with functional sequences transit and migrate through trigeminal neurons.

Patients with dementia are increasing with the aging of the population, and dementia has become a disease with high unmet medical needs. Glucagon-like peptide-1 (GLP-1), a neuropeptide, has been reported to improve learning and memory following intracerebroventricular administration. We focused on intranasal administration, which can deliver drugs noninvasively and efficiently to the brain. Although much of the human nasal mucosa is occupied by respiratory epithelium, many capillaries are present in the paracellular route of respiratory epithelium. Therefore, to incorporate GLP-1 into cells, we created a GLP-1 derivative by adding cell-penetrating peptides (CPP) and penetration accelerating sequences (PAS) to GLP-1. We investigated in vitro and in vivo function of PAS-CPP-GLP-1 to enable the translocation of GLP-1 directly from nose to brain. PAS-CPP-GLP-1 enhanced cellular uptake by macropinocytosis with CPP, efficiently escaped from the endosomes due to PAS, and exited the cells. PAS-CPP-GLP-1 also transited trigeminal nerve cells through axon transport and migrated to the adjacent trigeminal nerve cell. Moreover, PAS-CPP-GLP-1 showed significant improvement in learning memory in mice within 20 min of intranasal administration. These results suggested CPP and PAS may be important for the efficient transfer of GLP-1 to the site of action in the brain following intranasal administration.

[The Effects of Nanoparticles on Nerve Cell Differentiation and Its Mechanisms for Human Health Risk Analysis].

Neurodevelopment is one of the most complex events in human growth and is very sensitive to disruption. Various genetic factors are the main causes of neuronal dysfunction; however, recent epidemiological studies have also revealed relationships between environmental factors and the onset of neurodevelopmental disorders. Humans are regularly exposed to a wide range of environmental factors, among which fine particles have attracted recent interest. In this regards, the development of products containing nanomaterials has expanded substantially in a wide variety of fields including medicine, food, and cosmetics. As the size of the particles in these nanomaterials decreases, their reactivity at the tissue interface and their tissue penetration increases. In addition, the reduction of particle size could alter kinetics and lead to unexpected biological effects compared with those seen with conventional materials. Thus, we need to identify potential sources of unpredictable adverse effects of nanomaterials on neurodevelopment to ensure their safe use. From this perspective, nano-safety science research has been conducted through the collection of toxicity information on nanoparticles based on their physicochemical properties and kinetics via the association analysis of physicochemical properties, kinetics, and toxicity. The results of this nano-safety science research were then used in nano-safety design research to develop safer forms of nanomaterials. In this paper, we introduce findings that demonstrate that nanomaterials translocate into the brain and describe the effects on cranial nerves.

Influence of excessive sucrose consumption on exploratory behaviour in rats - Possible implications for the brain reward system.

Due to the low cost of production and the strong evolutionary preference for sweet taste in humans, sugar is added to many food products. This leads to often involuntary overconsumption of high amounts of sugar. Yet, growing evidence indicates that high-sugar diets impact brain function and impair cognitive ability. It may be due to physiological changes in specific regions of the brain or/and maladaptive changes in dopamine signalling similar to those observed in the etiology of addiction. In our study, rats from the experimental group were kept on a feeding protocol involving intermittent access to sucrose solution for eight weeks. Then, the animals underwent a spontaneous exploration test in an experimental arena divided into three zones where stationary and movable objects were placed. Studying the rats' exploratory behaviour allowed us to assess the impact of the sucrose diet on a broad spectrum of behaviours related to the general functioning of the organism in its environment. Analyses showed differences in reaction to novelty between different diet groups which had been placed in different experimental setups. Rats from the sugar-fed group responded to change with more pronounced exploratory behaviours directed at the source of the novel stimuli and the surrounding environment. These results may indicate a lower reward value of novelty resulting from diminished responsiveness of the reward system in the sugar-diet group. We have not found evidence for memory and/or learning impairments in rats on the sugar-rich diet.

Procedural and declarative memory brain systems in developmental language disorder (DLD).

The aim of the current study was to examine microstructural differences in white matter relevant to procedural and declarative memory between adolescents/young adults with and without Developmental Language Disorder (DLD) using diffusion tensor imaging (DTI). The findings showed atypical age-related changes in white matter structures in the corticostriatal system, in the corticocerebellar system, and in the medial temporal region in individuals with DLD. Results highlight the importance of considering the age factor in research on DLD. Future studies are needed to examine the developmental relationship between long-term memory and individual differences in language development and learning.

Tracking down a missing trigger for Alzheimer's disease by mass spectrometric imaging based on brain network analysis.

Alzheimer's disease (AD) has been proposed to begin in a cryptic form long before clinical symptoms appear. If this is the case, there might be an initial trigger leading to AD that we have not yet seen. Such a trigger might occur far away from the brain regions that are currently identified as affected sites, and might start long before either functional or histological changes are apparent. How might we detect this putative trigger? In this chapter, I propose an experimental approach using matrix-assisted laser desorption ionization (MALDI)-based imaging mass spectrometry (IMS), combined with pathological and functional connectivity studies, to track down the initial trigger of AD. The deficits in AD brains do not spread randomly, and even though we do not know where to find the initial deficit or which biomolecule is involved, the brain region where the initial change occurs is surely connected functionally to the brain regions that subsequently show detectable damage. Therefore, MALDI IMS taking account of the brain's functional connectivity and the spread of AD symptoms should be a powerful strategy for uncovering molecular signatures related to the AD trigger(s).

The aversive brain system of teleosts: Implications for neuroscience and biological psychiatry.

Defensive behavior is a function of specific survival circuits, the "aversive brain system", that are thought to be conserved across vertebrates, and involve threat detection and the organization of defensive responses to reduce or eliminate threat. In mammals, these circuits involve amygdalar and hypothalamic subnuclei and midbrain circuits. The increased interest in teleost fishes as model organisms in neuroscience created a demand to understand which brain circuits are involved in defensive behavior. Telencephalic and habenular circuits represent a "forebrain circuit" for threat processing and organization of responses, being important to mounting appropriate coping responses. Specific hypothalamic circuits organize neuroendocrine and neurovegetative outputs, but are the less well-studied in fish. A "midbrain circuit" is represented by projections to interneurons in the optic tectum which mediate fast escape responses via projections to the central gray and/or the brainstem escape network. Threatening stimuli (especially visual stimuli) can bypass the "high road" and directly activate this system, initiating escape responses. Increased attention to these circuits in an evolutionary framework is still needed.

Brain Connectivity Networks and the Aesthetic Experience of Music.

Listening to music is above all a human experience, which becomes an aesthetic experience when an individual immerses himself/herself in the music, dedicating attention to perceptual-cognitive-affective interpretation and evaluation. The study of these processes where the individual perceives, understands, enjoys and evaluates a set of auditory stimuli has mainly been focused on the effect of music on specific brain structures, as measured with neurophysiology and neuroimaging techniques. The very recent application of network science algorithms to brain research allows an insight into the functional connectivity between brain regions. These studies in network neuroscience have identified distinct circuits that function during goal-directed tasks and resting states. We review recent neuroimaging findings which indicate that music listening is traceable in terms of network connectivity and activations of target regions in the brain, in particular between the auditory cortex, the reward brain system and brain regions active during mind wandering.

Assessment of Behavioral Approach and Behavioral Inhibition Systems in Mood Disorders.

INTRODUCTION: Psychiatric disorders could be evaluated in terms of behavioral activation and inhibition systems. Dysregulation of these systems may lead to development of manic or depressive episodes in patients with mood disorders. This study aimed to identify Behavioral Approach System (BAS) and Behavioral Inhibition System (BIS) hypersensitivity as the functional brain system behaviors in patients with major depressive disorder and bipolar mood disorder I, compared to healthy individuals. METHODS: This case-control study was conducted in Razi Psychiatric Hospital, a mental health referral center in Northwest of Iran. The study consisted of two groups of patients, one with major depressive and the other with bipolar mood disorders and one healthy group. Each group had 40 patients (20 men and 20 women). The study data were collected through BIS and BAS questionnaire, Beck Depression Inventory (BDI-II), Young Mania Rating Scale (YMRS). The obtained data were analyzed by SPSS version 18. RESULTS: The findings showed a significant negative correlation between BIS, BAS and BAS subscales with the severity of depression and positive correlation with mania symptoms (P<0.05). CONCLUSION: BAS and BIS dysregulations may predispose people to mood disorder symptoms. BAS is hyperactive during manic phase and may predict the symptom severity of bipolar mood disorder.

Goal-Directed Behavior and Instrumental Devaluation: A Neural System-Level Computational Model.

Devaluation is the key experimental paradigm used to demonstrate the presence of instrumental behaviors guided by goals in mammals. We propose a neural system-level computational model to address the question of which brain mechanisms allow the current value of rewards to control instrumental actions. The model pivots on and shows the computational soundness of the hypothesis for which the internal representation of instrumental manipulanda (e.g., levers) activate the representation of rewards (or "action-outcomes", e.g., foods) while attributing to them a value which depends on the current internal state of the animal (e.g., satiation for some but not all foods). The model also proposes an initial hypothesis of the integrated system of key brain components supporting this process and allowing the recalled outcomes to bias action selection: (a) the sub-system formed by the basolateral amygdala and insular cortex acquiring the manipulanda-outcomes associations and attributing the current value to the outcomes; (b) three basal ganglia-cortical loops selecting respectively goals, associative sensory representations, and actions; (c) the cortico-cortical and striato-nigro-striatal neural pathways supporting the selection, and selection learning, of actions based on habits and goals. The model reproduces and explains the results of several devaluation experiments carried out with control rats and rats with pre- and post-training lesions of the basolateral amygdala, the nucleus accumbens core, the prelimbic cortex, and the dorso-medial striatum. The results support the soundness of the hypotheses of the model and show its capacity to integrate, at the system-level, the operations of the key brain structures underlying devaluation. Based on its hypotheses and predictions, the model also represents an operational framework to support the design and analysis of new experiments on the motivational aspects of goal-directed behavior.

Frontal brain dysfunction in alcoholism with and without antisocial personality disorder.

Alcoholism and antisocial personality disorder (ASPD) often are comorbid conditions. Alcoholics, as well as nonalcoholic individuals with ASPD, exhibit behaviors associated with prefrontal brain dysfunction such as increased impulsivity and emotional dysregulation. These behaviors can influence drinking motives and patterns of consumption. Because few studies have investigated the combined association between ASPD and alcoholism on neuropsychological functioning, this study examined the influence of ASPD symptoms and alcoholism on tests sensitive to frontal brain deficits. The participants were 345 men and women. Of them, 144 were abstinent alcoholics (66 with ASPD symptoms), and 201 were nonalcoholic control participants (24 with ASPD symptoms). Performances among the groups were examined with Trails A and B tests, the Wisconsin Card Sorting Test, the Controlled Oral Word Association Test, the Ruff Figural Fluency Test, and Performance subtests of the Wechsler Adult Intelligence Scale. Measures of affect also were obtained. Multiple regression analyses showed that alcoholism, specific drinking variables (amount and duration of heavy drinking), and ASPD were significant predictors of frontal system and affective abnormalities. These effects were different for men and women. The findings suggested that the combination of alcoholism and ASPD leads to greater deficits than the sum of each.