Differential Neuronal Activation Research Articles

Activity of estrogen receptor β expressing neurons in the medial amygdala regulates preference toward receptive females in male mice

The processing of information regarding the sex and reproductive state of conspecific individuals is critical for successful reproduction and survival in males. Generally, male mice exhibit a preference toward the odor of sexually receptive (RF) over nonreceptive females (XF) or gonadally intact males (IM). Previous studies suggested the involvement of estrogen receptor beta (ERβ) expressed in the medial amygdala (MeA) in male preference toward RF. To further delineate the role played by ERβ in the MeA in the neuronal network regulating male preference, we developed a new ERβ-iCre mouse line using the CRISPR-Cas9 system. Fiber photometry Ca2+ imaging revealed that ERβ-expressing neurons in the postero-dorsal part of the MeA (MeApd-ERβ+ neurons) were more active during social investigation toward RF compared to copresented XF or IM mice in a preference test. Chemogenetic inhibition of MeApd-ERβ+ neuronal activity abolished a preference to RF in "RF vs. XF," but not "RF vs. IM," tests. Analysis with cre-dependent retrograde tracing viral vectors identified the principal part of the bed nucleus of stria terminalis (BNSTp) as a primary projection site of MeApd-ERβ+ neurons. Fiber photometry recording in the BNSTp during a preference test revealed that chemogenetic inhibition of MeApd-ERβ+ neurons abolished differential neuronal activity of BNSTp cells as well as a preference to RF against XF but not against IM mice. Collectively, these findings demonstrate for the first time that MeApd-ERβ+ neuronal activity is required for expression of receptivity-based preference (i.e., RF vs. XF) but not sex-based preference (i.e., RF vs. IM) in male mice.

Differential Activation of Neurons of the Paraventricular Nucleus of the Hypothalamus in Response to Chronic Social Defeat Stress in Male Mice

Social adversity is a major contributor to chronic illnesses such as hypertension, obesity, and type-2 diabetes. Populations associated with lower social status are disproportionately affected by such illnesses, possibly due to recurrent exposure to social stress and adversity. Previous studies from our group and others have revealed that Chronic Social Defeat Stress (CSDS) in mice, which models the effects of low social status, results in anxiety-like behavior, endocrine abnormalities and cardiovascular perturbations. In this paradigm, intruder male C57BL/6J mice are placed in the home cage of larger, more aggressive Cd-1 male mice, and allowed to interact until the intruder is defeated and/or exhibits submissive behavior. The intruder is then housed within the resident cage for 24 hours, separated by a polycarbonate divider allowing for continuous sensory contact; this process is then repeated on a daily basis for several days. Of particular relevance, we have found that, over time, deleterious cardiovascular effects of CSDS are heightened, such that mice subjected to CSDS exhibit hypertension that increases in severity over time. Furthermore, corticosterone responses to the defeat session demonstrate plasticity with repeated exposure to social stress. Here, we hypothesized that activity within the paraventricular nucleus of the hypothalamus (PVN) may mediate altered physiological responses to defeat over time. The PVN contains neuroendocrine and pre-autonomic populations of neurons that produce oxytocin (OT), vasopressin (AVP), and corticotropin releasing hormone (CRH). Additionally, this region contains neurons which express the angiotensin type-1 receptor (AT1R) and increase blood pressure, at least in part, through release of CRH. To evaluate the impact of CSDS on neural activity within these specific PVN neuronal phenotypes, adult male C57BL/6J wild type mice or mice that expressed a variant of red fluorescent protein in cells that express (AT1R-tdTomato) were subjected to one or ten daily defeat sessions. Controls were handled similarly to defeated mice, but were not subjected to defeat. Ninety minutes after the initiation of the first or tenth defeat session, mice were euthanized and brains were processed to evaluate expression of c-Fos, a neuronal activation marker, in OT, AVP, and AT1R/CRH neurons, using a combination of immunohistochemistry and in situ hybridization. Compared to controls, one session of defeat resulted in elevated activation of OT and AVP neurons, as well as activation of AT1R/CRH neurons. Ten sessions of defeat robustly activated both OT and AT1R/CRH neurons compared to control conditions, while resulting in decreased activation of AVP neurons compared to one session of defeat. Collectively, these data suggest that mobilization of the PVN in response to social defeat stress may drive altered sympathetic and endocrine activity, contributing to cardiometabolic pathology. R01HL136595, R35HL150750, R01HL145028, R00HL125805, Florida Education Fund McKnight Fellowship This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Motor cortex gates distractor stimulus encoding in sensory cortex

Suppressing responses to distractor stimuli is a fundamental cognitive function, essential for performing goal-directed tasks. A common framework for the neuronal implementation of distractor suppression is the attenuation of distractor stimuli from early sensory to higher-order processing. However, details of the localization and mechanisms of attenuation are poorly understood. We trained mice to selectively respond to target stimuli in one whisker field and ignore distractor stimuli in the opposite whisker field. During expert task performance, optogenetic inhibition of whisker motor cortex increased the overall tendency to respond and the detection of distractor whisker stimuli. Within sensory cortex, optogenetic inhibition of whisker motor cortex enhanced the propagation of distractor stimuli into target-preferring neurons. Single unit analyses revealed that whisker motor cortex (wMC) decorrelates target and distractor stimulus encoding in target-preferring primary somatosensory cortex (S1) neurons, which likely improves selective target stimulus detection by downstream readers. Moreover, we observed proactive top-down modulation from wMC to S1, through the differential activation of putative excitatory and inhibitory neurons before stimulus onset. Overall, our studies support a contribution of motor cortex to sensory selection, in suppressing behavioral responses to distractor stimuli by gating distractor stimulus propagation within sensory cortex.

Differential Laminar Activation Dissociates Encoding and Retrieval in the Human Medial and Lateral Entorhinal Cortex.

The hierarchically organized structures of the medial temporal lobe are critically important for episodic memory function. Accumulating evidence suggests dissociable information processing pathways are maintained throughout these structures including in the medial and lateral entorhinal cortex. Cortical layers provide an additional dimension of dissociation as the primary input to the hippocampus derives from layer 2 neurons in the entorhinal cortex, whereas the deeper layers primarily receive output from the hippocampus. Here, novel high-resolution T2-prepared functional MRI methods were successfully used to mitigate susceptibility artifacts typically affecting MRI signals in this region providing uniform sensitivity across the medial and lateral entorhinal cortex. During the performance of a memory task, healthy human subjects (age 25-33 years, mean age 28.2 ± 3.3 years, 4 female) showed differential functional activation in the superficial and deep layers of the entorhinal cortex associated with task-related encoding and retrieval conditions, respectively. The methods provided here offer an approach to probe layer-specific activation in normal cognition and conditions contributing to memory impairment.SIGNIFICANCE STATEMENT This study provides new evidence for differential neuronal activation in the superficial versus deep layers of the entorhinal cortex associated with encoding and retrieval memory processes, respectively, in cognitively normal adults. The study further shows that this dissociation can be observed in both the medial and the lateral entorhinal cortex. The study was achieved by using a novel functional MRI method allowing us to measure robust functional MRI signals in both the medial and lateral entorhinal cortex that was not possible in previous studies. The methodology established here in healthy human subjects lays a solid foundation for subsequent studies investigating layer-specific and region-specific changes in the entorhinal cortex associated with memory impairment in various conditions such as Alzheimer's disease.

Vagus nerve stimulation parameters evoke differential neuronal responses in the locus coeruleus.

Vagus nerve stimulation (VNS) is used to treat drug-resistant epilepsy and depression, with additional applications under investigation. The noradrenergic center locus coeruleus (LC) is vital for VNS effects; however, the impact of varying stimulation parameters on LC activation is poorly understood. This study characterized LC activation across VNS parameters. Extracellular activity was recorded in rats' left LC while 11 VNS paradigms, utilizing variable frequencies and bursting characteristics, were pseudorandomly delivered to the left cervical vagus for five cycles. Neurons' change from baseline firing rate and timing response profiles were assessed. The proportion of neurons categorized as responders over 5 VNS cycles doubled in comparison to the first VNS cycle (p< 0.001) for all VNS paradigms, demonstrating an amplification effect. The percentage of positively consistent/positive responders increased for standard VNS paradigms with frequencies ≥10Hz and for bursting paradigms with shorter interburst intervals and more pulses per burst. The synchrony between pairs of LC neurons increased during bursting VNS but not standard paradigms. Also, the probability of evoking a direct response during bursting VNS was higher with longer interburst intervals and a higher number of pulses per burst. Standard paradigms between 10-30 Hz best positively activates LC with consistency to VNS while the best bursting paradigm to increase activity was 300 Hz, seven pulses per burst separated by 1s. Bursting VNS was effective in increasing synchrony between pairs of neurons, suggesting a common network recruitment originating from vagal afferents. These results indicate differential activation of LC neurons depending on the VNS parameters delivered.

In the back of your mind: Cortical mapping of paraspinal afferent inputs.

Topographic organisation is a hallmark of vertebrate cortex architecture, characterised by ordered projections of the body's sensory surfaces onto brain systems. High‐resolution functional magnetic resonance imaging (fMRI) has proven itself as a valuable tool to investigate the cortical landscape and its (mal‐)adaptive plasticity with respect to various body part representations, in particular extremities such as the hand and fingers. Less is known, however, about the cortical representation of the human back. We therefore validated a novel, MRI‐compatible method of mapping cortical representations of sensory afferents of the back, using vibrotactile stimulation at varying frequencies and paraspinal locations, in conjunction with fMRI. We expected high‐frequency stimulation to be associated with differential neuronal activity in the primary somatosensory cortex (S1) compared with low‐frequency stimulation and that somatosensory representations would differ across the thoracolumbar axis. We found significant differences between neural representations of high‐frequency and low‐frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral S1 sub‐regions, and in regions of the primary motor cortex (M1). High‐frequency stimulation preferentially activated Brodmann Area (BA) regions BA3a and BA4p, whereas low‐frequency stimulation was more encoded in BA3b and BA4a. Moreover, we found clear topographic differences in S1 for representations of the upper and lower back during high‐frequency stimulation. We present the first neurobiological validation of a method for establishing detailed cortical maps of the human back, which might serve as a novel tool to evaluate the pathological significance of neuroplastic changes in clinical conditions such as chronic low back pain.

Molecular and Cellular Adaptations in Hippocampal Parvalbumin Neurons Mediate Behavioral Responses to Chronic Social Stress.

Parvalbumin-expressing interneurons (PV neurons) maintain inhibitory control of local circuits implicated in behavioral responses to environmental stressors. However, the roles of molecular and cellular adaptations in PV neurons in stress susceptibility or resilience have not been clearly established. Here, we show behavioral outcomes of chronic social defeat stress (CSDS) are mediated by differential neuronal activity and gene expression in hippocampal PV neurons in mice. Using in vivo electrophysiology and chemogenetics, we find increased PV neuronal activity in the ventral dentate gyrus is required and sufficient for behavioral susceptibility to CSDS. PV neuron-selective translational profiling indicates mitochondrial oxidative phosphorylation is the most significantly altered pathway in stress-susceptible versus resilient mice. Among differentially expressed genes associated with stress-susceptibility and resilience, we find Ahnak, an endogenous regulator of L-type calcium channels which are implicated in the regulation of mitochondrial function and gene expression. Notably, Ahnak deletion in PV neurons impedes behavioral susceptibility to CSDS. Altogether, these findings indicate behavioral effects of chronic stress can be controlled by selective modulation of PV neuronal activity or a regulator of L-type calcium signaling in PV neurons.

Impact of Adolescent Intermittent Ethanol Exposure on Social Investigation, Social Preference, and Neuronal Activation in cFos-LacZ Male and Female Rats.

Adolescence is a sensitive developmental period during which alcohol use is often initiated and consumed in high quantities, often at binge or even high-intensity drinking levels. Our lab has repeatedly found that adolescent intermittent ethanol (AIE) exposure in rats results in long-lasting social impairments, specifically in males, however our knowledge of the neuronal underpinnings to this sex-specific effect of AIE is limited. The present study was designed to test whether social anxiety-like alterations in AIE-exposed males would be accompanied by alterations of neuronal activation across brain regions associated with social behavior, with AIE females demonstrating no social impairments and alterations in neuronal activation. Adolescent male and female cFos-LacZ transgenic rats on a Sprague-Dawley background were exposed to ethanol (4 g/kg, 25% v/v) or water via intragastric gavage every other day during postnatal days (P) 25–45 for a total of 11 exposures (n = 13 per group). Social behavior of adult rats was assessed on P70 using a modified social interaction test, and neuronal activation in brain regions implicated in social responding was assessed via β-galactosidase (β-gal) expression. We found that AIE exposure in males resulted in a significantly lower social preference coefficient relative to water-exposed controls, with no effect evident in females. Exposure-specific relationships between social behavior and neuronal activation were identified, with AIE eliminating correlations found in water controls related to social interaction, and eliciting negative correlations mainly in limbic regions in a sex-specific manner. AIE exposure in the absence of social testing was also found to differentially affect neural activity in the orbitofrontal cortex and central amygdala in males and females. These data suggest that AIE produces sex-specific social impairments that are potentially driven by differential neuronal activation states in regions important for social behavior, including the medial prefrontal and orbitofrontal cortices, nucleus accumbens, lateral septum, and central amygdala. Future studies should be focused on identification of specific neuronal phenotypes activated by interaction with a social partner in AIE-exposed subjects and their control counterparts.

A machine learning approach to characterize sequential movement-related states in premotor and motor cortices.

Nonhuman primate (NHP) movement kinematics have been decoded from spikes and local field potentials (LFPs) recorded during motor tasks. However, the potential of LFPs to provide network-like characterizations of neural dynamics during planning and execution of sequential movements requires further exploration. Is the aggregate nature of LFPs suitable to construct informative brain state descriptors of movement preparation and execution? To investigate this, we developed a framework to process LFPs based on machine-learning classifiers and analyzed LFP from a primate, implanted with several microelectrode arrays covering the premotor cortex in both hemispheres and the primary motor cortex on one side. The monkey performed a reach-to-grasp task, consisting of five consecutive states, starting from rest until a rewarding target (food) was attained. We use this five-state task to characterize neural activity within eight frequency bands, using spectral amplitude and pairwise correlations across electrodes as features. Our results show that we could best distinguish all five movement-related states using the highest frequency band (200-500 Hz), yielding an 87% accuracy with spectral amplitude, and 60% with pairwise electrode correlation. Further analyses characterized each movement-related state, showing differential neuronal population activity at above-γ frequencies during the various stages of movement. Furthermore, the topological distribution for the high-frequency LFPs allowed for a highly significant set of pairwise correlations, strongly suggesting a concerted distribution of movement planning and execution function is distributed across premotor and primary motor cortices in a specific fashion, and is most significant in the low ripple (100-150 Hz), high ripple (150-200 Hz), and multiunit frequency bands. In summary, our results show that the concerted use of novel machine-learning techniques with coarse grained queue broad signals such as LFPs may be successfully used to track and decode fine movement aspects involving preparation, reach, grasp, and reward retrieval across several brain regions.NEW & NOTEWORTHY Local field potentials (LFPs), despite lower spatial resolution compared to single-neuron recordings, can be used with machine learning classifiers to decode sequential movements involving motor preparation, execution, and reward retrieval. Our results revealed heterogeneity of neural activity on small spatial scales, further evidencing the utility of micro-electrode array recordings for complex movement decoding. With further advancement, high-dimensional LFPs may become the gold standard for brain-computer interfaces such as neural prostheses in the near future.

Susceptibility to express amphetamine locomotor sensitization correlates with dorsolateral striatum bursting activity and GABAergic synapses in the globus pallidus

Repeated psychostimulant administration results in behavioral sensitization, a process that is relevant in the early phases of drug addiction. Critically, behavioral sensitization is not observed in all subjects. Evidence shows that differential neuronal activity in the dorsolateral striatum (DLS) accompanies the expression of amphetamine (AMPH) locomotor sensitization. However, whether individual differences in DLS activity previous to AMPH administration can predict the expression of locomotor sensitization has not been assessed. Here, we examined DLS neuronal activity before and after repeated AMPH administration and related it to the susceptibility of rats to sensitize. For that, single-unit recordings on DLS medium spiny neurons (MSNs) were carried out in freely moving male Sprague Dawley rats during repeated AMPH administration. We also examined differences in neurostructure that could accompany sensitization. We quantified the density of the inhibitory postsynaptic marker gephyrin (Geph) in the entopeduncular nucleus (EP) and globus pallidus (GP). A higher burst firing and a lower percentage of correlation between MSNs post-Saline firing rate vs. locomotion predicted the expression of locomotor sensitization. Moreover, during the AMPH challenge, we observed that burst firing decreased in sensitized rats, in contrast to non-sensitized rats in which burst firing was maintained. Finally, a higher Geph density on GP but not EP was observed in non-sensitized rats after AMPH challenge. These results indicate that initial differences in DLS burst firing might underlie the susceptibility to express locomotor sensitization and suggest that the potentiation of dorsal striatum indirect pathway could be considered a protective mechanism to locomotor sensitization.

An Emerging Preventive Mental Health Care Strategy: The Neurobiological and Functional Basis of Positive Psychological Traits.

Even with the expanding burden of the COVID-19 pandemic on mental health, our approach to mental health care remains largely reactive rather than preventive. This trend is problematic because the majority of outpatient visits to primary care providers across the country is related to unmet mental health needs. Positive psychology has the potential to address these issues within mental health care and provide primary care providers with strategies to serve their patients more effectively. Positive psychology has many frameworks like hope, which can be measured using simple questionnaires in the waiting room. Moreover, there is a growing body of neurobiological evidence that lends credence to positive psychology concepts in the context of differential neuronal activation patterns. Many positive psychological instruments not only have high construct validity but also have connections to observable neurobiological differences tied to differences in psychosocial functioning. Despite the current evidence, we still need robust research that explores if such psychometric measurements and related interventions lead to clinically significant and favorable health outcomes in patients outside of controlled environments.

Differential Activation of Colonic Afferents and Dorsal Horn Neurons Underlie Stress-Induced and Comorbid Visceral Hypersensitivity in Female Rats

Chronic Overlapping Pain Conditions, including irritable bowel syndrome (IBS) and temporomandibular disorder (TMD), represent a group of idiopathic pain conditions that likely have peripheral and central mechanisms contributing to their pathology, but are poorly understood. These conditions are exacerbated by stress and have a female predominance. The presence of one condition predicts the presence or development of additional conditions, making this a significant pain management problem. The current study was designed to determine if the duration and magnitude of peripheral sensitization and spinal central sensitization differs between restraint stress-induced visceral hypersensitivity (SIH) and chronic comorbid pain hypersensitivity (CPH; stress during pre-existing orofacial pain). SIH in female rats, as determined by the visceromotor response, persisted at least four but resolved by seven weeks. In contrast, CPH persisted at least seven weeks. Surprisingly, colonic afferents in both SIH and CPH rats were sensitized at seven weeks. CPH rats also had referred pain through seven weeks, but locally anesthetizing the colon only attenuated the referred pain through four weeks, suggesting a transition to colonic afferent independent central sensitization. Different phenotypes of dorsal horn neurons were sensitized in the CPH rats seven weeks post stress compared to four weeks or SIH rats. The current study suggests differential processing of colonic afferent input to the lumbosacral spinal cord contributes to visceral hypersensitivity during comorbid chronic pain conditions. PerspectiveChronic Overlapping Pain Conditions represent a unique challenge in pain management. The diverse nature of peripheral organs hinders a clear understanding of underlying mechanisms accounting for the comorbidity. This study highlights a mismatch between the condition-dependent behavior and peripheral and spinal mechanisms that contribute to visceral pain hypersensitivity.

Tactile modulation of memory and anxiety requires dentate granule cells along the dorsoventral axis

Touch can positively influence cognition and emotion, but the underlying mechanisms remain unclear. Here, we report that tactile experience enrichment improves memory and alleviates anxiety by remodeling neurons along the dorsoventral axis of the dentate gyrus (DG) in adult mice. Tactile enrichment induces differential activation and structural modification of neurons in the dorsal and ventral DG, and increases the presynaptic input from the lateral entorhinal cortex (LEC), which is reciprocally connected with the primary somatosensory cortex (S1), to tactile experience-activated DG neurons. Chemogenetic activation of tactile experience-tagged dorsal and ventral DG neurons enhances memory and reduces anxiety respectively, whereas inactivation of these neurons or S1-innervated LEC neurons abolishes the beneficial effects of tactile enrichment. Moreover, adulthood tactile enrichment attenuates early-life stress-induced memory deficits and anxiety-related behavior. Our findings demonstrate that enriched tactile experience retunes the pathway from S1 to DG and enhances DG neuronal plasticity to modulate cognition and emotion.

Call-specific patterns of neural activation in auditory processing of Richardson's ground squirrel alarm calls.

IntroductionRichardson's ground squirrels use alarm calls to warn conspecifics about potential predatory threats. Chirp calls typically indicate high levels of threat from airborne predators, while whistle calls are associated with lower levels of threat from terrestrial predators. These types of calls primarily elicit escape behaviors and increased vigilance in receivers, respectively. While much is known about the neural mechanisms involved in the production of vocalizations, less is known about the mechanisms important for the perception of alarm calls by receivers, and whether changes in perceived risk are associated with unique patterns of neuronal activation. Thus, to determine whether alarm calls associated with different levels of predation risk result in differential neuronal activation, we used immunohistochemistry to identify and quantify c‐Fos immunopositive cells in brain regions important in stress, fear, danger, and reward, following alarm call reception.MethodsWe exposed 29 female Richardson's ground squirrels (10 control, 10 whistle receivers, and 9 chirp receivers) to playbacks of whistles, chirps, or a no‐vocalization control. We then assessed neuronal activation via c‐Fos immunohistochemistry in 12 brain regions.ResultsGround squirrels receiving high‐threat “chirp” vocalizations had reduced neuronal activation in the medial amygdala and superior colliculus compared with controls. It is likely that changes in activity in these brain regions serve to alter the balance between approach and avoidance in turn promoting escape behaviors.ConclusionsThus, we conclude that in Richardson's ground squirrels, these brain regions are important for the perception of risk resulting from receiving alarm calls and allow for appropriate behavioral responses by receivers.

Cathodic-leading pulses are more effective than anodic-leading pulses in intracortical microstimulation of the auditory cortex

Objective. Intracortical microstimulation (ICMS) is widely used in neuroscientific research. Earlier work from our lab showed the possibility to combine ICMS with neuronal recordings on the same shank of multi-electrode arrays and consequently inside the same cortical column in vivo. The standard stimulus pulse shape for ICMS is a symmetric, biphasic current pulse. Here, we investigated the role of the leading-phase polarity (cathodic- versus anodic-leading) of such single ICMS pulses on the activation of the cortical network. Approach. Local field potentials (LFPs) and multi-unit responses were recorded in the primary auditory cortex (A1) of adult guinea pigs (n = 15) under ketamine/xylazine anesthesia using linear multi-electrode arrays. Physiological responses of A1 were recorded during acoustic stimulation and ICMS. For the ICMS, the leading-phase polarity, the stimulated electrode and the stimulation current where varied systematically on any one of the 16 electrodes while recording at the same time with the 15 remaining electrodes. Main results. Cathodic-leading ICMS consistently led to higher response amplitudes. In superficial cortical layers and for a given current amplitude, cathodic-leading and anodic-leading ICMS showed comparable activation patterns, while in deep layers only cathodic-leading ICMS reliably generated local neuronal activity. ICMS had a significantly smaller dynamic range than acoustic stimulation regardless of leading-phase polarity. Significance. The present study provides in vivo evidence for a differential neuronal activation mechanism of the different leading-phase polarities, with cathodic-leading stimulation being more effective, and suggests that the waveform of the stimulus should be considered systematically for cortical neuroprosthesis development.

P25. Time specific neuronal activation and its association with cognitive control over emotions

Introduction Successful cognitive control over emotions (CCE) can impede a biased attention towards negative valenced information (‘Negativity Bias’, NB) which can be observed in various psychiatric disorders. On a neurophysiological level CCE and the NB can be investigated with event related potentials (ERPs). The goal of the current study is to investigate the NB and CCE with ERPs on feedback as its emotional valence is largely based on the interpretation by the participant. Methods Healthy participants (n = 24) performed an adaptive version of a 2-back Paced Auditory Serial Addition Task (PASAT), a difficult working memory task, that challenges CCE and which is linked to increases of negative feelings. Feedback was given by presenting green (red) light after correct (incorrect) responses. Simultaneously continuous EEG was recorded. Since we were interested in the ERP elicited by the emotional meaning of red and green feedback as opposed to a differential neuronal activation to red and green light per se, we conducted a control task which comprised the mere presentation of red and green light. The stimulus locked ERPs from that task were subtracted from the PASAT ERPs. Results For the feedback related negativity (FRN, 200–300 ms post-feedback), an ERP linked to feedback processing and affective reactions to feedback we could find a bigger negativity for negative (red) compared to positive (green) feedback. Furthermore, we could find a significant correlation of this difference and the PASAT performance. A smaller FRN (negative-positive feedback) was associated with a better performance. For the P300 (300–400 ms post-feedback), an ERP associated with attention allocation, we could not find a difference between negative and positive feedback. However, we observed that a larger P300 by negative as compared to positive feedback is linked with better performance. For the Late Positive Potential (LPP, 400–1000 ms post-feedback), an event related potential which captures attention shifts towards emotional information, we could find a bigger positivity for negative feedback compared to positive feedback but no significant correlation of this difference with the PASAT performance. However, we could find a correlation of Δ LPP (negative-positive feedback) with the percentage of consecutive correct trials, another indicator for successful cognitive control. Conclusion These results indicate that in early phases, of feedback processing, which are more driven by the emotional salience of the feedback, less automatic attention allocation towards negative as compared to positive feedback is associated with a better CCE. In contrast, in later phases, it seems as if a bigger cognitive effort and therefore bigger feedback specific neuronal activation is linked to an increased CCE. Further implications of the study will be discussed.

Neonatal Sevoflurane Exposure Induces Adulthood Fear-induced Learning Disability and Decreases Glutamatergic Neurons in the Basolateral Amygdala

Neonatal mice exposed to sevoflurane show certain cognitive and behavioral impairments in adulthood. However, the mechanisms underlying long-term cognitive deficits induced by sevoflurane exposure remain unknown. The present study was performed to investigate whether there is differential neuronal activation between naive mice and sevoflurane-exposed neonates in fear-conditioning tests based on immediate early gene (c-Fos) expression. Male mice were exposed to 3% sevoflurane (SEVO group) or carrier gas alone (no anesthesia, NA group) for 6 hours on postnatal day 6. The mice were allowed to mature before performing the contextual fear-conditioning test. A reduced freezing response was confirmed in the SEVO group. Neural activation in the regions of the medial prefrontal cortex, hippocampus, and amygdala was investigated using c-Fos immunostaining 2 hours after the test. The types of neurons activated were also identified. The number of c-Fos-positive cells decreased by 27% in the basolateral amygdala in the SEVO group, while no significant changes were observed in other regions. Furthermore, glutamatergic, but not γ-aminobutyric acid (GABA)ergic, neurons expressed c-Fos after the contextual fear-conditioning test in both groups. The number of glutamatergic neurons in the basolateral amygdala in the SEVO group was reduced by 27%. Decreased neural activation in the basolateral amygdala may be associated with reduced freezing time in neonatal sevoflurane-exposed mice. Fewer glutamatergic neurons responding to fear stimuli in the basolateral amygdala may contribute to decreased neural activation and learning deficits in mice exposed to sevoflurane as neonates.

Regulation of Brown Adipose Tissue Activity by Interoceptive CNS Pathways: The interaction between Brain and Periphery.

To maintain thermal homeostasis, specific thermogenic tissues are under the control of central thermoregulatory networks that regulate the body's response to thermal challenges. One of these mechanisms involves non-shivering thermogenesis in brown adipose tissue (BAT), which is activated in cold environments in order to defend the body against physical damage as a result of hypothermia. The objective of our study was to assess the interaction between CNS thermoregulatory pathways and sympathetic innervation in BAT during a cold exposure paradigm. Our results show that an innocuous whole-body cooling paradigm induces significant differences in fMRI BOLD signal at the location of the right anterior insula and the red nucleus/substantia nigra region, between lean subjects with high levels of sympathetic innervation in supraclavicular BAT (BAT+ group), and subjects with low levels of sympathetic innervation (BAT− group). Specifically, results indicate significantly larger fMRI BOLD signal changes between periods of cooling and warming of the skin in the BAT+ (as compared to BAT−) group at the location of the right anterior insula. In contrast, the BAT+ group showed significantly smaller fMRI BOLD signal changes in the midbrain between periods of skin cooling and warming. Our findings are consistent with a hierarchical thermoregulatory control system that involves the initiation of inhibitory signals from the right anterior insula toward midbrain areas that normally exert tonic inhibition on the medullary raphe, from where BAT is directly innervated. Our data suggests that exposure to cold elicits differential neuronal activity in interoceptive regulatory centers of subjects with high and low level of sympathetic innervation. As a result, the variability of cold-activated BAT mass observed in humans might be, in part, yoked to different sensitivities of interoceptive cortical brain areas to skin temperature changes.

Insertable NO/CO Microsensors Recording Gaseous Vasomodulators Reflecting Differential Neuronal Activation Level with Respect to Seizure Focus.

Nitric oxide (NO) and carbon monoxide (CO) are important signaling molecules shaping vasomodulation. This paper reports simultaneous in vivo monitoring of NO, CO and dendritic summation of action potential at three different cortical regions: seizure focus and two additional places, vertically and horizontally separated by 1.2 mm from the seizure focus, during epileptic seizure induced by 4-aminopyrindine injection. An amperometric dual microsensor having a high spatiotemporal resolution monitored fast and dynamic changes of NO and CO, and neural changes were recorded with a glass pipet electrode for local field potential (LFP). At all three locations, onsets and offsets of NO and CO changes well synchronized with fast LFP changes, while the patterns and concentrations of NO and CO changes were varied depending on the sensing locations. The insertable NO/CO dual microsensor was successful to measure intimately linked NO and CO in acute seizure events with high sensitivity, selectivity, and spatiotemporal resolution.

Targeted Stimulation Using Differences in Activation Probability across the Strength–Duration Space

Electrical stimulation is ubiquitous as a method for activating neuronal tissue, but there is still significant room for advancement in the ability of these electrical devices to implement smart stimulus waveform design to more selectively target populations of neurons. The capability of a device to encode more complicated and precise messages to a neuronal network greatly increases if the stimulus input space is broadened to include variable shaped waveforms and multiple stimulating electrodes. The relationship between a stimulating electrode and the activated population is unknown; a priori. For that reason, the population of excitable neurons must be characterized in real-time and for every combination of stimulating electrodes and neuronal populations. Our automated experimental system allows investigation into the stimulus-evoked neuronal response to a current pulse using dissociated neuronal cultures grown atop microelectrode arrays (MEAs). The studies presented here demonstrate that differential activation is achievable between two neurons using either multiple stimulating electrodes or variable waveform shapes. By changing the aspect ratio of a rectangular current pulse; the stimulus activated neurons in the strength–duration (SD) waveform space with differing probabilities. Additionally, in the case when two neuronal activation curves intersect each other in the SD space; one neuron can be selectively activated with short-pulse-width; high-current stimuli while the other can be selectively activated with long-pulse-width; low-current stimuli. Exploring the capabilities and limitations of electrical stimulation allows for improvements to the delivery of stimulus pulses to activate neuronal populations. Many state-of-the-art research and clinical stimulation solutions, including those using a single microelectrode, can benefit from waveform design methods to improve stimulus efficacy. These findings have even greater import into multi-electrode systems because spatially distributed electrodes further enhance accessibility to differential neuronal activation.