Decrease In Neuronal Activity Research Articles

Research advances in the role of dopaminergic neurons involved in emergence from general anesthesia

Background Dopamine plays an important role in learning and memory, arousal, emotion and motor control. Recent studies found that dopaminergic (DA) neurons are also involved in both induction and emergence of general anesthesia. But the underlying mechanism is unclear. Objective To review the potential mechanisms underlying DA regulation of the emergence from general anesthesia. Content Midbrain DA neurons are densely distributed in the ventral tegmental area(VTA) and the substantia nigra pars compacta(SNc), where mesolimbic/mesocortical and mesostriatal DA pathways respectively originate. Genetic and pharmacological enhancement of the DA pathways promotes arousal. In contrast, knock-out of dopamine receptors or ablation of VTA abolishes the arousal effect of dopamine. Recordings of the activity of VTA DA neurons show an increase or a decrease in neuronal activity when subjects are in awake or sleeping state. It is putatively accepted that general anesthesia shares similar electroencephalographic signatures with sleep, so does emergence of general anesthesia with arousal. Several optogenetic studies reveal that activating VTA DA neurons facilitates the emergence of general anesthesia. Similarly, electrical stimuli in the VTA, instead of in the SNc, shortens the delay of the emergence from general anesthesia. Therefore, VTA DA neurons may have greater impact on the recovery from general anesthesia than SNc DA neurons. Trend DA are involved in the emergence from general anesthesia, and stimulating VTA DA neurons may provide a means to accelerate the recovery of general anesthesia. Key words: Dopaminergic neuron; Anesthesia, general; Consciousness recovery; Arousal

In Vivo Visualization of Active Polysynaptic Circuits With Longitudinal Manganese-Enhanced MRI (MEMRI).

Manganese-enhanced magnetic resonance imaging (MEMRI) is a powerful tool for in vivo non-invasive whole-brain mapping of neuronal activity. Mn2+ enters active neurons via voltage-gated calcium channels and increases local contrast in T1-weighted images. Given the property of Mn2+ of axonal transport, this technique can also be used for tract tracing after local administration of the contrast agent. However, MEMRI is still not widely employed in basic research due to the lack of a complete description of the Mn2+ dynamics in the brain. Here, we sought to investigate how the activity state of neurons modulates interneuronal Mn2+ transport. To this end, we injected mice with low dose MnCl2 2. (i.p., 20 mg/kg; repeatedly for 8 days) followed by two MEMRI scans at an interval of 1 week without further MnCl2 injections. We assessed changes in T1 contrast intensity before (scan 1) and after (scan 2) partial sensory deprivation (unilateral whisker trimming), while keeping the animals in a sensory enriched environment. After correcting for the general decay in Mn2+ content, whole brain analysis revealed a single cluster with higher signal in scan 1 compared to scan 2: the left barrel cortex corresponding to the right untrimmed whiskers. In the inverse contrast (scan 2 > scan 1), a number of brain structures, including many efferents of the left barrel cortex were observed. These results suggest that continuous neuronal activity elicited by ongoing sensory stimulation accelerates Mn2+ transport from the uptake site to its projection terminals, while the blockage of sensory-input and the resulting decrease in neuronal activity attenuates Mn2+ transport. The description of this critical property of Mn2+ dynamics in the brain allows a better understanding of MEMRI functional mechanisms, which will lead to more carefully designed experiments and clearer interpretation of the results.

Increasing adult hippocampal neurogenesis in mice after exposure to unpredictable chronic mild stress may counteract some of the effects of stress

Major depression is hypothesized to be associated with dysregulations of the hypothalamic–pituitary–adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic corticosterone is sufficient to protect against its harmful effects on behavior. However, it is an open question if increasing AHN after the onset of chronic stress exposure would be able to rescue behavioral deficits and which mechanisms might be involved in recovery. We investigated this question by using a 10-week unpredictable chronic mild stress (UCMS) model on a transgenic mouse line (iBax mice), in which the pro-apoptotic gene Bax can be inducibly ablated in neural stem cells following Tamoxifen injection, therefore enhancing the survival of newborn neurons in the adult brain. We did not observe any effect of our treatment in non-stress conditions, but we did find that increasing AHN after 2 weeks of UCMS is sufficient to counteract the effects of UCMS on certain behaviors (splash test and changes in coat state) and endocrine levels and thus to display some antidepressant-like effects. We observed that increasing AHN lowered the elevated basal corticosterone levels in mice exposed to UCMS. This was accompanied by a tamoxifen-induced reversal of the lack of stress-induced decrease in neuronal activation in the anteromedial division of the bed nucleus of the stria terminalis (BSTMA) after intrahippocampal dexamethasone infusion, pointing to a possible mechanism through which adult-born neurons might have exerted their effects. Our results contribute to the neurogenesis hypothesis of depression by suggesting that increasing AHN may be beneficial not just before, but also after exposure to stress by counteracting several of its effects, in part through regulating the HPA axis.

Bisphenol A exposure perturbs visual function of adult cats by remodeling the neuronal activity in the primary visual pathway.

Bisphenol A (BPA), a common environmental xenoestrogen, has been implicated in physiological and behavioral impairment, but the neuronal basis remains elusive. Although various synaptic mechanisms have been shown to mediate BPA-induced brain deficits, there are almost no reports addressing its underlying physiological mechanisms at the individual neuron level, particularly in the primary visual system. In the present study, using multiple-channel recording technique, we recorded the responses of single neurons in the primary visual system of cats to various direction stimuli both before and after BPA exposure. The results showed that the orientation selectivity of neurons in the primary visual cortex (area 17, A17) was obviously decreased after 2h of intravenous BPA administration (0.2mg/kg). Moreover, there were worse performances of information transmission of A17 neurons, presenting markedly decreased signal-to-noise ratio (SNR). To some extent, these functional decreases were attributable to the altered information inputs from lateral geniculate nucleus (LGN), which showed an increased spontaneous activity. Additionally, local injection of BPA (3.3μg/ml) in A17 resulted in an obvious increase in orientation selectivity and a decrease in neuronal activity, involving enhanced activity of fast-spiking inhibitory interneurons. In conclusion, our results first demonstrate that acute BPA exposure can restrict the visual perception of cats, mainly depending on the alteration of the LGN projection, not the intercortical interaction. Importantly, BPA-induced-brain deficits might not only be confined to the cortical level but also occur as early as at the subcortical level.

Rodent Medial Frontal Control of Temporal Processing in the Dorsomedial Striatum.

Although frontostriatal circuits are critical for the temporal control of action, how time is encoded in frontostriatal circuits is unknown. We recorded from frontal and striatal neurons while rats engaged in interval timing, an elementary cognitive function that engages both areas. We report four main results. First, "ramping" activity, a monotonic change in neuronal firing rate across time, is observed throughout frontostriatal ensembles. Second, frontostriatal activity scales across multiple intervals. Third, striatal ramping neurons are correlated with activity of the medial frontal cortex. Finally, interval timing and striatal ramping activity are disrupted when the medial frontal cortex is inactivated. Our results support the view that striatal neurons integrate medial frontal activity and are consistent with drift-diffusion models of interval timing. This principle elucidates temporal processing in frontostriatal circuits and provides insight into how the medial frontal cortex exerts top-down control of cognitive processing in the striatum.SIGNIFICANCE STATEMENT The ability to guide actions in time is essential to mammalian behavior from rodents to humans. The prefrontal cortex and striatum are critically involved in temporal processing and share extensive neuronal connections, yet it remains unclear how these structures represent time. We studied these two brain areas in rodents performing interval-timing tasks and found that time-dependent "ramping" activity, a monotonic increase or decrease in neuronal activity, was a key temporal signal. Furthermore, we found that striatal ramping activity was correlated with and dependent upon medial frontal activity. These results provide insight into information-processing principles in frontostriatal circuits.

0128 SENSORY DEPRIVATION SUPPRESSES CORTICAL ACTIVITY IN A STATE AND ENVIRONMENT DEPENDENT MANNER

Monocular deprivation (MD), a well-established tool for studying plasticity in the visual cortex, induces a biphasic response in neural activity. Initially, neuronal firing rates (FRs) are suppressed by widespread Hebbian LTD. Following FR suppression in extended MD, homeostatic mechanisms restore spiking precisely to baseline levels. We recently demonstrated that the homeostatic return to the set-point is expressed during waking and not sleep. Here we address the role of arousal-states and environmental variables in gating the Hebbian depression of activity that characterizes early MD. To answer this question, we recorded activity from ensembles of cortical single units in juvenile rats (postnatal days 24–34) continuously for 10 days during a monocular deprivation (MD) paradigm. As expected, amongst neurons that were “online” for the at least the first 6 days of the recording, firing rates dropped during early MD. Under normal conditions (12:12 light/dark cycles), automatically detected decreases in neuronal activity clustered around the ZT0 (“lights on”) and a significantly greater portion of the decrease occurred during light hours than dark. To further probe this causality of dark to light transitions in initiating the FR depression, we manipulated the light cycles of animals at critical points in early MD. Preliminary data suggest that animals must be awake for the FR suppression to start, but subsequent sleep/wake states are not correlated with changes in FR. Cortical activity in control hemispheres was stable across light/dark transitions. Taken with our previous data, these results suggest that individual forms of cortical plasticity have specific environmental and behavioral rules governing their expression and segregation. 1K99NS089800-01 (KBH) R01EY014439 (GGT).

Functional changes in the reward circuit in response to gaming-related cues after training with a commercial video game

In the present longitudinal study, we aimed to investigate video game training associated neuronal changes in reward processing using functional magnetic resonance imaging (fMRI). We recruited 48 healthy young participants which were assigned to one of 2 groups: A group in which participants were instructed to play a commercial video game (“Super Mario 64 DS”) on a portable Nintendo DS handheld console at least 30minutes a day over a period of two months (video gaming group; VG) or to a matched passive control group (CG). Before and after the training phase, in both groups, fMRI imaging was conducted during passively viewing reward and punishment-related videos sequences recorded from the trained video game. The results show that video game training may lead to reward related decrease in neuronal activation in the dorsolateral prefrontal cortex (DLPFC) and increase in the hippocampus. Additionally, the decrease in DLPFC activation was associated with gaming related parameters experienced during playing. Specifically, we found that in the VG, gaming related parameters like performance, experienced fun and frustration (assessed during the training period) were correlated to decrease in reward related DLPFC activity. Thus, neuronal changes in terms of video game training seem to be highly related to the appetitive character and reinforcement schedule of the game. Those neuronal changes may also be related to the often reported video game associated improvements in cognitive functions.

Role of the Lateral Habenula in Pain-Associated Depression.

Patients with chronic pain have significantly higher incidences of depression and anxiety than the average person. However, the mechanism underlying this link has not been elucidated in terms of how chronic pain causes significant mood changes and further develops into severe anxiety or depression. The serotonergic system in the raphe nuclei is an important component in both pain processing and the pathogenesis of depression. Since the lateral habenular nucleus (LHb) controls the raphe nuclei, it may participate in the regulation of pain-associated depression. Thus, the aim of the current study was to investigate the role of the LHb in this pathophysiological process. We used chronic constriction injury (CCI) of the sciatic nerve in rats as a model for neuropathic pain and assessed the changes potentially related to the mood disorders. The forced swim test (FST) and sucrose preference test (SPT) were performed to determine the behavioral changes 28 days after pain surgery. Expression of β calmodulin-dependent protein kinase type II (βCaMKII) in the LHb, cytochrome-c oxidase (COX) activity in the LHb and dorsal raphe nucleus (DRN) and serotonin (5-HT) levels in the DRN were measured. We found an increasing in LHb activity and βCaMKII expression, and a decrease in neuronal activity in the DRN and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratios in the CCI rats. These effects were accompanied by the depression-like behaviors. Lesions in the LHb improved the pain threshold and depression-like behavior in the rats. These results suggest that the LHb may play a role in pain-associated depression by affecting the activity of 5-HT neurons in the DRN. Furthermore, we showed that increases in the LHb-DRN pathway activity were a common neurobiological mechanisms for pain and depression, which may explain the coexistence of pain and depression.

Characteristics of breathing rate control mediated by a subregion within the pontine parabrachial complex.

The role of the dorsolateral pons in the control of expiratory duration (Te) and breathing frequency is incompletely understood. A subregion of the pontine parabrachial-Kölliker-Fuse (PB-KF) complex of dogs was identified via microinjections, in which localized pharmacologically induced increases in neuronal activity produced increases in breathing rate while decreases in neuronal activity produced decreases in breathing rate. This subregion is also very sensitive to local and systemic opioids. The purpose of this study was to precisely characterize the relationship between the PB-KF subregion pattern of altered neuronal activity and the control of respiratory phase timing as well as the time course of the phrenic nerve activity/neurogram (PNG). Pulse train electrical stimulation patterns synchronized with the onset of the expiratory (E) and/or phrenic inspiratory (I) phase were delivered via a small concentric bipolar electrode while the PNG was recorded in decerebrate, vagotomized dogs. Step frequency patterns during the E phase produced a marked frequency-dependent decrease in Te, while similar step inputs during the I phase increased inspiratory duration (Ti) by 14 ± 3%. Delayed pulse trains were capable of pacing the breathing rate by terminating the E phase and also of triggering a consistent stereotypical inspiratory PNG pattern, even when evoked during apnea. This property suggests that the I-phase pattern generator functions in a monostable circuit mode with a stable E phase and a transient I phase. Thus the I-pattern generator must contain neurons with nonlinear pacemaker-like properties, which allow the network to rapidly obtain a full on-state followed by relatively slow inactivation. The activated network can be further modulated and supplies excitatory drive to the neurons involved with pattern generation.NEW & NOTEWORTHY A circumscribed subregion of the pontine medial parabrachial nucleus plays a key role in the control of breathing frequency primarily via changes in expiratory duration. Excitation of this subregion triggers the onset of the inspiratory phase, resulting in a stereotypical ramplike phrenic activity pattern independent of time within the expiratory phase. The ability to pace the I-burst rate suggests that the in vivo I-pattern generating network must contain functioning pacemaker neurons.

Longitudinal Positron Emission Tomography in Preventive Alzheimer's Disease Drug Trials, Critical Barriers from Imaging Science Perspective.

Recent Alzheimer's trials have recruited cognitively normal people at risk for Alzheimer's dementia. Due to the lack of clinical symptoms in normal population, conventional clinical outcome measures are not suitable for these early trials. While several groups are developing new composite cognitive tests that could serve as potential outcome measures by detecting subtle cognitive changes in normal people, there is a need for longitudinal brain imaging techniques that can correlate with temporal changes in these new tests and provide additional objective measures of neuropathological changes in brain. Positron emission tomography (PET) is a nuclear medicine imaging procedure based on the measurement of annihilation photons after positron emission from radiolabeled molecules that allow tracking of biological processes in body, including the brain. PET is a well‐established in vivo imaging modality in Alzheimer's disease diagnosis and research due to its capability of detecting abnormalities in three major hallmarks of this disease. These include (1) amyloid beta plaques; (2) neurofibrillary tau tangles and (3) decrease in neuronal activity due to loss of nerve cell connection and death. While semiquantitative PET imaging techniques are commonly used to set discrete cut‐points to stratify abnormal levels of amyloid accumulation and neurodegeneration, they are suboptimal for detecting subtle longitudinal changes. In this study, we have identified and discussed four critical barriers in conventional longitudinal PET imaging that may be particularly relevant for early Alzheimer's disease studies. These include within and across subject heterogeneity of AD‐affected brain regions, PET intensity normalization, neuronal compensations in early disease stages and cerebrovascular amyloid deposition.

Single and Multiple Change Point Detection in Spike Trains: Comparison of Different CUSUM Methods.

In a natural environment, sensory systems are faced with ever-changing stimuli that can occur, disappear or change their properties at any time. For the animal to react adequately the sensory systems must be able to detect changes in external stimuli based on its neuronal responses. Since the nervous system has no prior knowledge of the stimulus timing, changes in stimulus need to be inferred from the changes in neuronal activity, in particular increase or decrease of the spike rate, its variability, and shifted response latencies. From a mathematical point of view, this problem can be rephrased as detecting changes of statistical properties in a time series. In neuroscience, the CUSUM (cumulative sum) method has been applied to recorded neuronal responses for detecting a single stimulus change. Here, we investigate the applicability of the CUSUM approach for detecting single as well as multiple stimulus changes that induce increases or decreases in neuronal activity. Like the nervous system, our algorithm relies exclusively on previous neuronal population activities, without using knowledge about the timing or number of external stimulus changes. We apply our change point detection methods to experimental data obtained by multi-electrode recordings from turtle retinal ganglion cells, which react to changes in light stimulation with a range of typical neuronal activity patterns. We systematically examine how variations of mathematical assumptions (Poisson, Gaussian, and Gamma distributions) used for the algorithms may affect the detection of an unknown number of stimulus changes in our data and compare these CUSUM methods with the standard Rate Change method. Our results suggest which versions of the CUSUM algorithm could be useful for different types of specific data sets.

Dynamic DNA methylation controls glutamate receptor trafficking and synaptic scaling.

Hebbian plasticity, including long-term potentiation and long-term depression, has long been regarded as important for local circuit refinement in the context of memory formation and stabilization. However, circuit development and stabilization additionally relies on non-Hebbian, homeostatic, forms of plasticity such as synaptic scaling. Synaptic scaling is induced by chronic increases or decreases in neuronal activity. Synaptic scaling is associated with cell-wide adjustments in postsynaptic receptor density, and can occur in a multiplicative manner resulting in preservation of relative synaptic strengths across the entire neuron's population of synapses. Both active DNA methylation and demethylation have been validated as crucial regulators of gene transcription during learning, and synaptic scaling is known to be transcriptionally dependent. However, it has been unclear whether homeostatic forms of plasticity such as synaptic scaling are regulated via epigenetic mechanisms. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously largely considered separately: DNA methylation, homeostatic plasticity, and glutamate receptor trafficking. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously considered separately: glutamate receptor trafficking, DNA methylation, and homeostatic plasticity.

Notoginsenoside R1 increases neuronal excitability and ameliorates synaptic and memory dysfunction following amyloid elevation.

Neurodegeneration and synaptic dysfunction observed in Alzheimer's disease (AD) have been associated with progressive decrease in neuronal activity. Here, we investigated the effects of Notoginsenoside R1 (NTR1), a major saponin isolated from Panax notoginseng, on neuronal excitability and assessed the beneficial effects of NTR1 on synaptic and memory deficits under the Aβ-enriched conditions in vivo and in vitro. We assessed the effects of NTR1 on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular and intracellular recording techniques. We found that NTR1 increased the membrane excitability of CA1 pyramidal neurons in hippocampal slices by lowering the spike threshold possibly through a mechanism involving in the inhibition of voltage-gated K+ currents. In addition, NTR1 reversed Aβ1-42 oligomers-induced impairments in long term potentiation (LTP). Reducing spontaneous firing activity with 10 nM tetrodotoxin (TTX) abolished the protective effect of NTR1 against Aβ-induced LTP impairment. Finally, oral administration of NTR1 improved the learning performance of the APP/PS1 mouse model of AD. Our work reveals a novel mechanism involving in modulation of cell strength, which contributes to the protective effects of NTR1 against Aβ neurotoxicity.

The Glucose Concentration‐Dependency of Spontaneous Activity in a Cultured Neuronal Network

SUMMARYCultured rat hippocampal network on a multielectrode array (MEA) dish is a useful model for analyzing network electrical dynamics and its developmental changes. Neurons autonomously form a complex network on an MEA dish and spontaneous electrical activity is often observed without any input from the external world. The spontaneous activity is generated by synaptic interactions between neurons and reflects an internal biochemical state of a whole neuronal network. The origin of electrical activity is electrochemical potential generated by active transport of ions, which requires catabolism of ATP. We elucidated the relationship between spontaneous electrical activity and external glucose concentration. The spontaneous activity changed transiently, depending on glucose concentrations. The number of electrical spikes in spontaneous activity increases depending on the concentration of external glucose concentration. Interestingly, this increase is not only suppressed but turn to decrease. In the case of glucose concentration is 17.56 mM, the number of activity is the most, and then it decreases in the case of glucose concentration is more than 20 mM. In addition, the decrease of neuronal activity at a high glucose concentration is not influenced by the blockade of inhibitory synaptic activity. These results suggest that a cultured neuronal network has optimal glucose concentration 17.56 mM, which corresponds to the concentration of glucose in a culture medium.

Mint Proteins Are Required for Synaptic Activity-dependent Amyloid Precursor Protein (APP) Trafficking and Amyloid β Generation

Aberrant amyloid β (Aβ) production plays a causal role in Alzheimer disease pathogenesis. A major cellular pathway for Aβ generation is the activity-dependent endocytosis and proteolytic cleavage of the amyloid precursor protein (APP). However, the molecules controlling activity-dependent APP trafficking in neurons are less defined. Mints are adaptor proteins that directly interact with the endocytic sorting motif of APP and are functionally important in regulating APP endocytosis and Aβ production. We analyzed neuronal cultures from control and Mint knockout neurons that were treated with either glutamate or tetrodotoxin to stimulate an increase or decrease in neuronal activity, respectively. We found that neuronal activation by glutamate increased APP endocytosis, followed by elevated APP insertion into the cell surface, stabilizing APP at the plasma membrane. Conversely, suppression of neuronal activity by tetrodotoxin decreased APP endocytosis and insertion. Interestingly, we found that activity-dependent APP trafficking and Aβ generation were blocked in Mint knockout neurons. We showed that wild-type Mint1 can rescue APP internalization and insertion in Mint knockout neurons. In addition, we found that Mint overexpression increased excitatory synaptic activity and that APP was internalized predominantly to endosomes associated with APP processing. We demonstrated that presenilin 1 (PS1) endocytosis requires interaction with the PDZ domains of Mint1 and that this interaction facilitates activity-dependent colocalization of APP and PS1. These findings demonstrate that Mints are necessary for activity-induced APP and PS1 trafficking and provide insight into the cellular fate of APP in endocytic pathways essential for Aβ production.

The Glucose Concentration-dependency of Spontaneous Activity in a Cultured Neuronal Network

Cultured rat hippocampal network on a multi electrode array (MEA) dish is a useful model for analyzing network electrical dynamics and its developmental changes. Neurons autonomously form a complex network on a MEA dish and spontaneous electrical activity is often observed without any input from the external world. The spontaneous activity is generated by synaptic interactions between neurons and reflects an internal biochemical state of a whole neuronal network. The origin of electrical activity is electrochemical potential generated by active transport of ions, which requires catabolism of ATP. We elucidated the relationship between spontaneous electrical activity and external glucose concentration. The spontaneous activity changed transiently, depending on glucose concentrations. The number of electrical spikes in spontaneous activity increases depending on the concentration of external glucose concentration. Interestingly, this increase is not only suppressed but turn to decrease. In the case of glucose concentration is 17.56 mM, the number of activity is the most, and then it decreases in the case of glucose concentration is more than 20 mM. In addition, the decrease of neuronal activity at a high glucose concentration is not influenced by the blockade of inhibitory synaptic activity. These results suggest that a cultured neuronal network has optimal glucose concentration 17.56 mM, which corresponds to the concentration of glucose in a culture medium.

High-Resolution fMRI Reveals Laminar Differences in Neurovascular Coupling between Positive and Negative BOLD Responses

The six cortical layers have distinct anatomical andphysiological properties, like different energy use and different feedforward and feedback connectivity. It is not known if and how layer-specific neural processes are reflected in the fMRI signal. To address this question we used high-resolution fMRI to measure BOLD, CBV, and CBF responses to stimuli that elicit positive and negative BOLD signals in macaque primary visual cortex. We found that regions with positive BOLD responses had parallel increases in CBV and CBF, whereas areas with negative BOLD responses showed a decrease in CBF but an increase in CBV. For positive BOLD responses, CBF and CBV increased in the center of the cortex, but for negative BOLD responses, CBF decreased superficially while CBV increased in the center. Our findings suggest different mechanisms for neurovascular coupling for BOLD increases and decreases, aswell as laminar differences in neurovascular coupling.

Excitatory and inhibitory mechanisms underlying somatosensory habituation

Habituation is a basic process of learning in which repeated exposure to a sensory stimulus leads to a decrease in the strength of neuronal activations and behavioral responses. In addition to increases in neuronal activity, sensory stimuli can also lead to decreases in neuronal activity. Until now, the effects of habituation on stimulus-induced neuronal deactivations have not been investigated. We performed functional magnetic resonance imaging in 30 healthy subjects during repetitive unilateral somatosensory stimulation and combined this analysis with a psychophysiological examination of changes in the perception threshold. Consistent with the literature, we found a time-dependent decrease of the positive blood oxygenation level-dependent (BOLD) response (indicative of habituation) in the primary somatosensory cortex (SI) contralateral to the stimulus. In contrast, the negative BOLD response (NBR) in the ipsilateral SI did not show a decrease in amplitude; instead, an increase in amplitude was found, i.e., a stronger NBR (increased response). The increased NBR was associated with an increased perception threshold of the nonstimulated hand. These findings suggest that habituation is not primarily characterized by a decrease in the neuronal response to repeated stimuli but rather a widespread change in the balance between excitatory and inhibitory effects that favors inhibitory effects.

On the origin of sustained negative BOLD response

Several brain regions exhibit a sustained negative BOLD response (NBR) during specific tasks, as assessed with functional magnetic resonance imaging. The origin of the NBR and the relationships between the vascular/metabolic dynamics and the underlying neural activity are highly debated. Converging evidence indicates that NBR, in human and non-human primates, can be interpreted in terms of decrease in neuronal activity under its basal level, rather than a purely vascular phenomenon. However, the scarcity of direct experimental evidence suggests caution and encourages the ongoing utilization of multimodal approaches in the investigation of this effect.

Acute and chronic methylphenidate modulates the neuronal activity of the caudate nucleus recorded from freely behaving rats

Methylphenidate (MPD) is currently one of the most prescribed drug therapies for attention deficit/hyperactivity disorder (ADHD) and moreover is abused for cognitive enhancement and used for recreation by the young and adults. Methylphenidate is used for prolonged periods of time and its mechanism of action on the brain is still unknown. The main action of MPD is known to act on the motive circuit of the brain, and one of these structures is the caudate nucleus (CN). The objective of this study was to investigate the neurophysiological properties of the CN neurons in response to acute and chronic administration of MPD in freely behaving animals, previously implanted with permanent semi microelectrodes. Twenty-six rats were permanently implanted with semi microelectrodes into the CN using general anesthesia. On experimental day one (ED1) the rat was placed into the testing chamber, and neuronal activity was recorded using a wireless (telemetric) headstage device following both a saline and a 2.5 mg/kg MPD injection. From ED2 to ED6 daily injections of 2.5 mg/kg MPD were administered without recordings to induce a chronic effect of the drug, preceded by three days of washout (ED7-ED9) where no injections were given. On ED10 rats were placed back into the testing chamber, the wireless headstage device was attached to skull cap and recordings were resumed for 1 h each following both a saline and re-challenge administration of 2.5 mg/kg MPD. Sixty-seven CN neuronal recorded units from twenty-six animals with identical shape and amplitude at ED1 and ED10 were evaluated. All the 67 CN units responded to MPD administration, 70% (47/67) CN units exhibited an increase in activity following initial 2.5 mg/kg MPD administration and 30% (20/67) exhibited a decrease in neuronal activity. On ED10 all the CN units showed a significant change in their firing rate baseline compared to ED1 baseline, 52% (35/67) exhibiting an increase in their ED10 baseline activity compared to ED1 baseline activity and 48% (32/67) of the CN units at ED10 exhibited decreasing activity. All the CN units responded significantly to MPD rechallenge at ED10, 57% (38/67) of the units exhibited increased neuronal activity while 43% (29/67) exhibited decreasing neuronal activity. The results indicate that the majority of the CN units exhibited neurophysiological sensitization.