Activation In Midbrain Research Articles

Neurovascular and immune factors of vulnerability of substantia nigra dopaminergic neurons in non-human primates

Dopaminergic neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson’s disease (PD), while those in the dorsal tier and ventral tegmental area are relatively spared. The factors determining why these neurons are more vulnerable than others are still unrevealed. Neuroinflammation and immune cell infiltration have been demonstrated to be a key feature of neurodegeneration in PD. However, the link between selective dopaminergic neuron vulnerability, glial and immune cell response, and vascularization and their interactions has not been deciphered. We aimed to investigate the contribution of glial cell activation and immune cell infiltration in the selective vulnerability of ventral dopaminergic neurons within the midbrain in a non-human primate model of PD. Structural characteristics of the vasculature within specific regions of the midbrain were also evaluated. Parkinsonian monkeys exhibited significant microglial and astroglial activation in the whole midbrain, but no major sub-regional differences were observed. Remarkably, the ventral substantia nigra was found to be typically more vascularized compared to other regions. This feature might play some role in making this region more susceptible to immune cell infiltration under pathological conditions, as greater infiltration of both T- and B- lymphocytes was observed in parkinsonian monkeys. Higher vascular density within the ventral region of the SNc may be a relevant factor for differential vulnerability of dopaminergic neurons in the midbrain. The increased infiltration of T- and B- cells in this region, alongside other molecules or toxins, may also contribute to the susceptibility of dopaminergic neurons in PD.

Differential optogenetic activation of the auditory midbrain in freely moving behaving mice.

In patients with severe auditory impairment, partial hearing restoration can be achieved by sensory prostheses for the electrical stimulation of the central nervous system. However, these state-of-the-art approaches suffer from limited spectral resolution: electrical field spread depends on the impedance of the surrounding medium, impeding spatially focused electrical stimulation in neural tissue. To overcome these limitations, optogenetic activation could be applied in such prostheses to achieve enhanced resolution through precise and differential stimulation of nearby neuronal ensembles. Previous experiments have provided a first proof for behavioral detectability of optogenetic activation in the rodent auditory system, but little is known about the generation of complex and behaviorally relevant sensory patterns involving differential activation. In this study, we developed and behaviorally tested an optogenetic implant to excite two spatially separated points along the tonotopy of the murine inferior colliculus (ICc). Using a reward based operant Go/No-Go paradigm, we show that differential optogenetic activation of a sub-cortical sensory pathway is possible and efficient. We demonstrate how animals which were previously trained in a frequency discrimination paradigm (a) rapidly respond to either sound or optogenetic stimulation, (b) generally detect optogenetic stimulation of two different neuronal ensembles, and (c) discriminate between them. Our results demonstrate that optogenetic excitatory stimulation at different points of the ICc tonotopy elicits a stable response behavior over time periods of several months. With this study, we provide the first proof of principle for sub-cortical differential stimulation of sensory systems using complex artificial cues in freely moving animals.

Hippocampal convergence during anticipatory midbrain activation promotes subsequent memory formation

The hippocampus has been a focus of memory research since H.M’s surgery abolished his ability to form new memories, yet its mechanistic role in memory remains debated. Here, we identify a candidate memory mechanism: an anticipatory hippocampal “convergence state”, observed while awaiting valuable information, and which predicts subsequent learning. During fMRI, participants viewed trivia questions eliciting high or low curiosity, followed seconds later by its answer. We reasoned that encoding success requires a confluence of conditions, so that hippocampal states more conducive to memory formation should converge in state space. To operationalize convergence of neural states, we quantified the typicality of multivoxel patterns in the medial temporal lobes during anticipation and encoding of trivia answers. We found that the typicality of anticipatory hippocampal patterns increased during high curiosity. Crucially, anticipatory hippocampal pattern typicality increased with dopaminergic midbrain activation and uniquely accounted for the association between midbrain activation and subsequent recall. We propose that hippocampal convergence states may complete a cascade from motivation and midbrain activation to memory enhancement, and may be a general predictor of memory formation.

Pharmacological modulation of ventral tegmental area neurons elicits changes in trigeminovascular sensory processing and is accompanied by glycemic changes: Implications for migraine.

Imaging migraine premonitory studies show increased midbrain activation consistent with the ventral tegmental area, an area involved in pain modulation and hedonic feeding. We investigated ventral tegmental area pharmacological modulation effects on trigeminovascular processing and consequent glycemic levels, which could be involved in appetite changes in susceptible migraine patients. Serotonin and pituitary adenylate cyclase-activating polypeptide receptors immunohistochemistry was performed in ventral tegmental area parabrachial pigmented nucleus of male Sprague Dawley rats. In vivo trigeminocervical complex neuronal responses to dura mater nociceptive electrical stimulation, and facial mechanical stimulation of the ophthalmic dermatome were recorded. Changes in trigeminocervical complex responses following ventral tegmental area parabrachial pigmented nucleus microinjection of glutamate, bicuculline, naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole were measured, and blood glucose levels assessed pre- and post-microinjection. Glutamatergic stimulation of ventral tegmental area parabrachial pigmented nucleus neurons reduced nociceptive and spontaneous trigeminocervical complex neuronal firing. Naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole inhibited trigeminovascular spontaneous activity, and trigeminocervical complex neuronal responses to dural-evoked electrical and mechanical noxious stimulation. Trigeminovascular sensory processing through modulation of the ventral tegmental area parabrachial pigmented nucleus resulted in reduced circulating glucose levels. Pharmacological modulation of ventral tegmental area parabrachial pigmented nucleus neurons elicits changes in trigeminovascular sensory processing. The interplay between ventral tegmental area parabrachial pigmented nucleus activity and the sensory processing by the trigeminovascular system may be relevant to understand associated sensory and homeostatic symptoms in susceptible migraine patients.

Activity in the Dorsomedial Striatum Underlies Serial Reversal Learning Performance Under Probabilistic Uncertainty

BackgroundCorticostriatal circuits, particularly the dorsomedial striatum (DMS) and lateral orbitofrontal cortex, are critical for navigating reversal learning under probabilistic uncertainty. These same areas are implicated in the reversal learning impairments observed in individuals with psychosis as well as their psychotic symptoms, suggesting that they may share a common neurobiological substrate. To address this question, we used psychostimulant exposure and specific activation of the DMS during reversal learning in mice to assess corticostriatal activity. MethodsWe used amphetamine treatment to induce psychosis-relevant neurobiology in male mice during reversal learning and to examine pathway-specific corticostriatal activation. To determine the causal role of DMS activity, we used chemogenetics to drive midbrain inputs during a range of probabilistic contingencies. ResultsMice treated with amphetamine showed altered punishment learning, which was associated with decreased shifting after losses and increased perseverative errors after reversals. Reversal learning performance and strategies were dependent on increased activity in lateral orbitofrontal cortex to DMS circuits as well as in the DMS itself. Specific activation of midbrain to DMS circuits also decreased shifting after losses and reversal learning performance. However, these alterations were dependent on the probabilistic contingency. ConclusionsOur work suggests that the DMS plays a multifaceted role in reversal learning. Increasing DMS activity impairs multiple reversal learning processes dependent on the level of uncertainty, confirming its role in the maintenance and selection of incoming cortical inputs. Together, these outcomes suggest that elevated dopamine levels in the DMS could contribute to decision-making impairments in individuals with psychosis.

A Linear Superposition Model of Envelope and Frequency Following Responses May Help Identify Generators Based on Latency.

Envelope and frequency-following responses (FFRENV and FFRTFS) are scalp-recorded electrophysiological potentials that closely follow the periodicity of complex sounds such as speech. These signals have been established as important biomarkers in speech and learning disorders. However, despite important advances, it has remained challenging to map altered FFRENV and FFRTFS to altered processing in specific brain regions. Here we explore the utility of a deconvolution approach based on the assumption that FFRENV and FFRTFS reflect the linear superposition of responses that are triggered by the glottal pulse in each cycle of the fundamental frequency (F0 responses). We tested the deconvolution method by applying it to FFRENV and FFRTFS of rhesus monkeys to human speech and click trains with time-varying pitch patterns. Our analyses show that F0ENV responses could be measured with high signal-to-noise ratio and featured several spectro-temporally and topographically distinct components that likely reflect the activation of brainstem (<5 ms; 200-1000 Hz), midbrain (5-15 ms; 100-250 Hz), and cortex (15-35 ms; ~90 Hz). In contrast, F0TFS responses contained only one spectro-temporal component that likely reflected activity in the midbrain. In summary, our results support the notion that the latency of F0 components map meaningfully onto successive processing stages. This opens the possibility that pathologically altered FFRENV or FFRTFS may be linked to altered F0ENV or F0TFS and from there to specific processing stages and ultimately spatially targeted interventions.

A multisynaptic pathway from the ventral midbrain toward spinal motoneurons in monkeys.

Motivation boosts motor performance. Activity of the ventral midbrain (VM), consisting of the ventral tegmental area (VTA), the substantia nigra pars compacta (SNc) and the retrorubral field (RRF), plays an important role in processing motivation. However, little is known about the neural substrate bridging the VM and the spinal motor output. We hypothesized that the VM might exert a modulatory influence over the descending motor pathways. By retrograde transneuronal labelling with rabies virus, we demonstrated the existence of multisynaptic projections from the VM to the cervical enlargement in monkeys. The distribution pattern of spinal projection neurons in the VM exhibited a caudorostral gradient, in that the RRF and the caudal part of the SNc contained more retrogradely labelled neurons than the VTA and the rostral part of the SNc. Electrical stimulation of the VM induced muscle responses in the contralateral forelimb with a delay of a few milliseconds following the responses of the ipsilateral primary motor cortex (M1). The magnitude and number of evoked muscle responses were associated with the stimulus intensity and number of pulses. The muscle responses were diminished during M1 inactivation. Thus, the present study has identified a multisynaptic VM–spinal pathway that is mediated, at least in part, by the M1 and might play a pivotal role in modulatory control of the spinal motor output.Key points Motivation to obtain reward is thought to boost motor performance, and activity in the ventral midbrain is important to the motivational process.Little is known about a neural substrate bridging the ventral midbrain and the spinal motor output.Retrograde trans‐synaptic experiments revealed that the ventral midbrain projects multisynaptically to the spinal cord in macaque monkeys.Ventral midbrain activation by electrical stimulation generated cortical activity in the motor cortex and forelimb muscle activity.A multisynaptic ventral midbrain–spinal pathway most probably plays a pivotal role in modulatory control of the spinal motor output.

Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM).

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation. In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue). Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms. These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise. The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI.

Neural response to aggressive and positive interactions in violent offenders and nonviolent individuals.

BackgroundDue to its severe negative consequences, human violence has been targeted by a vast number of studies. Yet, neurobiological mechanisms underlying violence are still widely unclear and it seems necessary to aim for high ecological validity to learn about mechanisms contributing to violence in real life.MethodsThe present functional magnetic resonance imaging (fMRI) study investigated the neurofunction of individuals with a history of violent offenses compared with that of controls using a laboratory paradigm requesting individuals to empathically engage in videos depicting provocative aggressive and positive social interactions from a first‐person perspective.ResultsThe contrast of aggressive vs. positive scenarios revealed midbrain activation patterns associated with caudal periaqueductal gray (PAG) in violent offenders; In controls, the rostral PAG was involved. Additionally, only in controls, this contrast revealed an involvement of the amygdaloidal complex. Moreover, in violent offenders the contrast of positive vs. aggressive situations revealed an involvement of areas in the insula, post‐central gyrus and anterior cingulate cortex.ConclusionsOur results support findings on the differential role of PAG subdivisions in response to threat and point to altered processing of positive social interactions in violent offenders. They further support the notion that changes in PAG recruitment might contribute to violent individuals “taking action” instead of freezing in case of threatening situations.

Christian Faith View On Mid-Brain Activation System And Its Impact On The Spirituality Of Children Aged 6 To 12 Years Old In Surabaya

God created humans as the most special creation compared to His other creations. Human intelligence is caused by one organ which, although small in size, has a very vital role, namely the brain. Advances in knowledge and technology have encouraged scientists to try solving the mysteries of the brain. Many studies have focused on the right brain and left brain, or to balance the right brain and left brain. But in recent years, there has been a training/self-development institute who stated that they had found a way to balance the right and left brain, namely by activating the midbrain. This midbrain activation method is aimed at children aged 5-15 years because it is considered that children at this age are more easily activated in a very short time through a computer.The method used in writing this work is a Literature Study that contains various information on matters related to the topic of discussion. In addition to using literature, writing will be complemented by field research, using a Check List to interview respondents. The research approach used are qualitative and quantitative approach. A The qualitative approach obtains data regarding respondent's experiences. This writing has the aim of finding ( knowing ) whether the Midbrain Activation system is in accordance with God's Word or against God's Word; to open the horizons of parents, congregations and even readers of this paper, especially those with children, so that they can be more careful in choosing training for their children.

The relationship between cognitive ability and BOLD activation across sleep-wake states.

The sleep spindle, a waxing and waning oscillation in the sigma frequency range, has been shown to correlate with fluid intelligence; i.e. the ability to use logic, learn novel rules/patterns, and solve problems. Using simultaneous EEG and fMRI, we previously identified the neural correlates of this relationship, including activation of the thalamus, bilateral putamen, medial frontal gyrus, middle cingulate cortex, and precuneus. However, research to date has focussed primarily on non-rapid eye movement (NREM) sleep, and spindles per se, thus overlooking the possibility that brain activity that occurs in other sleep-wake states might also be related to cognitive abilities. In our current study, we sought to investigate whether brain activity across sleep/wake states is also related to human intelligence in N = 29 participants. During NREM sleep, positive correlations were observed between fluid intelligence and blood oxygen level dependent (BOLD) activations in the bilateral putamen and the paracentral lobule/precuneus, as well as between short-term memory (STM) abilities and activity in the medial frontal cortex and inferior frontal gyrus. During wake, activity in bilateral postcentral gyri and occipital lobe was positively correlated with short-term memory abilities. In participants who experienced REM sleep in the scanner, fluid intelligence was positively associated with midbrain activation, and verbal intelligence was associated with right postcentral gyrus activation. These findings provide evidence that the relationship between sleep and intellectual abilities exists beyond sleep spindles.

Presbycusis

Presbycusis is aging deafness, progressive decrease in hearing, high frequency usually associated with tinnitus. This is due to the release of free radicals in cellular metabolism leading to cell death of cochlear hair cells, stria vascularis, and sensorineural degeneration. It also leads to vasoconstriction of end arteries resulting in hypoxia, ischemia, and necrosis of cells. Apart from hair cells, rest all can be regenerated by suitable environment, diet positivity, lifestyle changes, and proper diet along with Yoga and Pranayama. It is a long-run exercise. Since visual integration is a part of hearing, focused concentration, dynamic neurobics, and mid-brain activation also help in rehabilitation. The most important Pranayama is modified Nadi Shodhan (Kumbhak).

The Assessment of Brain Functional Changes in the Temporal Lobe Epilepsy Patient with Cognitive Impairment by Resting-state Functional Magnetic Resonance Imaging.

Objectives:The objective of the study was to detect functional changes in the brain of cognitive impairment-temporal lobe epilepsy (CI-TLE) patient and to sort out the possible mechanism involved in CI in CI-TLE patients using resting-state functional magnetic resonance imaging (RS-fMRI).Material and Methods:Fifty-eight TLE cases were included, which was divided into 44 TLE patients without CI (cognitive not impairment [CNI]-TLE) and 14 TLE patients with CI (CI-TLE). The normal control (NC) group consisted of 40 participants. RS-fMRI data preprocessing was carried out in statistical parametric mapping (SPM) software. The data were realigned, coregistered, normalized, and finally smoothened and then were taken for amplitude of low-frequency fluctuation (ALFF) calculation in RS-fMRI data analysis toolkit (REST) software. For data analysis, voxel-wise two-sample t-test was carried out between TLE group and NC group; CI-TLE group and cognitive not impairment-TLE (CNI-TLE) group in SPM software, a cluster >10 voxels and P < 0.01 was considered to be significant.Results:Compared to NC, the TLE patients showed increased ALFF activation mostly in parahippocampal gyrus (PG), frontal lobe, midbrain, pons, insula, inferior temporal gyrus, and anterior cingulate gyrus (ACG) while decreased ALFF value was seen in posterior cingulate gyrus, cuneus, cerebellum posterior lobe, inferior parietal lobule (IPL), and superior temporal gyrus. Compared to CNI-TLE, CI-TLE patients showed increased ALFF in middle temporal gyrus (MTG), cuneus, ACG, IPL, middle frontal gyrus (MFG), superior frontal gyrus (SFG), cerebellum posterior lobe, and decreased ALFF cluster in the corpus callosum and MFG.Conclusion:Between TLE and NC, we found increased ALFF activation in PG, frontal lobe, thalamus, insula, midbrain, and pons in TLE patient. Between CI and CNI TLE, area of executive control network and default model network, especially in MTG, ACG, IPL, MFG, and SFG, had increased ALFF value in CI-TLE patient. Activation of these areas should be because of the decompensation mechanism.

Rosmarinic acid attenuates inflammatory responses through inhibiting HMGB1/TLR4/NF-κB signaling pathway in a mouse model of Parkinson's disease

Inflammation contributes to the pathological processes in patients and animal models of PD. Rosmarinic acid (RA) has been demonstrated to protect neurons in PD models. The present study aimed to evaluate the anti-inflammatory effect of RA on PD and reveal possible pharmacological mechanisms. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) was injected to mice to establish PD model in vivo. BV-2 cells were exposed to 1-methyl-4-phenylpyridinium (MPP+) and α-synuclein to establish PD model in vitro. Results showed that treatment with RA dose-dependently improved motor function of PD mice, increased the number of tyrosine hydroxylase-positive cells, reduced production of pro-inflammatory cytokines, and inhibited microglia activation in ventral midbrain. In cell study, RA also decreased MPP+ or α-synuclein-induced secretion of pro-inflammatory cytokines. Furthermore, RA treatment downregulated the expression levels of HMGB1, TLR4 and Myd88 and inhibited NF-κB nuclear expression both in PD animal and cell models. These findings indicated that RA could attenuate inflammatory responses through suppressing HMGB1/TLR4/NF-κB signaling pathway, which may contribute to its anti-PD activity.

The Innate Alarm System and Subliminal Threat Presentation in Posttraumatic Stress Disorder: Neuroimaging of the Midbrain and Cerebellum

Background The innate alarm system, a network of interconnected midbrain, other brainstem, and thalamic structures, serves to rapidly detect stimuli in the environment prior to the onset of conscious awareness. This system is sensitive to threatening stimuli and has evolved to process these stimuli subliminally for hastened responding. Despite the conscious unawareness, the presentation of subliminal threat stimuli generates increased activation of limbic structures, including the amygdala and insula, as well as emotionally evaluative structures, including the cerebellum and orbitofrontal cortex. Posttraumatic stress disorder (PTSD) is associated with an increased startle response and decreased extinction learning to conditioned threat. The role of the innate alarm system in the clinical presentation of PTSD, however, remains poorly understood. Methods Here, we compare midbrain, brainstem, and cerebellar activation in persons with PTSD (n = 26) and matched controls (n = 20) during subliminal threat presentation. Subjects were presented with masked trauma-related and neutral stimuli below conscious threshold. Contrasts of subliminal brain activation for the presentation of neutral stimuli were subtracted from trauma-related brain activation. Group differences in activation, as well as correlations between clinical scores and PTSD activation, were examined. Imaging data were preprocessed utilizing the spatially unbiased infratentorial template toolbox within SPM12. Results Analyses revealed increased midbrain activation in PTSD as compared to controls in the superior colliculus, periaqueductal gray, and midbrain reticular formation during subliminal threat as compared to neutral stimulus presentation. Controls showed increased activation in the right cerebellar lobule V during subliminal threat presentation as compared to PTSD. Finally, a negative correlation emerged between PTSD patient scores on the Multiscale Dissociation Inventory for the Depersonalization/Derealization subscale and activation in the right lobule V of the cerebellum during the presentation of subliminal threat as compared to neutral stimuli. Conclusion We interpret these findings as evidence of innate alarm system overactivation in PTSD and of the prominent role of the cerebellum in the undermodulation of emotion observed in PTSD.

Food addiction distinguishes an overweight phenotype that can be reversed by low calorie diet.

Similarities in neural activation patterns in obese and substance-dependent subjects led to the food addiction concept, but studies exploiting this issue for obesity stratification are missing. We assessed brain activation in response to food cues using 18 F-2-fluoro-2-deoxy-glucose-PET in 36 overweight women, stratified by low or high food addiction groups according to the Yale Food Addiction Scale (YFAS). Assessments were repeated after a 3-month diet. We found greater activation in thalamus, hypothalamus, midbrain, putamen, and occipital cortex (reward), but not in prefrontal and orbitofrontal cortices (control/reward receipt) in the high-YFAS versus low-YFAS group. In high-YFAS subjects, orbitofrontal responsiveness was inversely related to YFAS severity and hunger rating, and positive associations were observed between regional brain activation and lipid intake. A 3-month diet abolished group differences in brain activation. Our data suggest that food addiction distinguishes an overweight phenotype that can be reversed by diet, opening to personalized strategies in obesity treatment.

A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

Intrinsically regulated learning is modulated by synaptic dopamine signaling.

We recently provided evidence that an intrinsic reward-related signal-triggered by successful learning in absence of any external feedback-modulated the entrance of new information into long-term memory via the activation of the dopaminergic midbrain, hippocampus, and ventral striatum (the SN/VTA-Hippocampal loop; Ripollés et al., 2016). Here, we used a double-blind, within-subject randomized pharmacological intervention to test whether this learning process is indeed dopamine-dependent. A group of healthy individuals completed three behavioral sessions of a language-learning task after the intake of different pharmacological treatments: a dopaminergic precursor, a dopamine receptor antagonist or a placebo. Results show that the pharmacological intervention modulated behavioral measures of both learning and pleasantness, inducing memory benefits after 24 hr only for those participants with a high sensitivity to reward. These results provide causal evidence for a dopamine-dependent mechanism instrumental in intrinsically regulated learning and further suggest that subject-specific reward sensitivity drastically alters learning success.

Astrocyte Hypertrophy and Microglia Activation in the Rat Auditory Midbrain Is Induced by Electrical Intracochlear Stimulation.

Neuron–glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron–glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation.

Abscopal Activation of Microglia in Embryonic Fish Brain Following Targeted Irradiation with Heavy-Ion Microbeam.

Microglia remove apoptotic cells by phagocytosis when the central nervous system is injured in vertebrates. Ionizing irradiation (IR) induces apoptosis and microglial activation in embryonic midbrain of medaka (Oryzias latipes), where apolipoprotein E (ApoE) is upregulated in the later phase of activation of microglia In this study, we found that another microglial marker, l-plastin (lymphocyte cytosolic protein 1), was upregulated at the initial phase of the IR-induced phagocytosis when activated microglia changed their morphology and increased motility to migrate. We further conducted targeted irradiation to the embryonic midbrain using a collimated microbeam of carbon ions (250 μm diameter) and found that the l-plastin upregulation was induced only in the microglia located in the irradiated area. Then, the activated microglia might migrate outside of the irradiated area and spread through over the embryonic brain, expressing ApoE and with activated morphology, for longer than 3 days after the irradiation. These findings suggest that l-plastin and ApoE can be the biomarkers of the activated microglia in the initial and later phase, respectively, in the medaka embryonic brain and that the abscopal and persisted activation of microglia by IR irradiation could be a cause of the abscopal and/or adverse effects following irradiation.