Relay Nuclei Research Articles

Connectivity between nidopallium caudolateral and visual pathways in color perception of zebra finches

Researchers demonstrated an elegant ability for red discrimination in zebra finches. It is interested to understand whether red activates exhibit much stronger response than other colors in neural network levels. To reveal the question, local field potentials (LFPs) was recorded and analyzed in two visual pathways, the thalamofugal and the tectofugal pathways, of zebra finches. Human studies demonstrate visual associated telencephalons communicate with higher order brain areas such as prefrontal cortex. The present study determined whether a comparable transmission occurs in zebra finches. Telencephalic regions of the thalamofugal (the visual Wulst) and the tectofugal pathway (the entopallium) with their higher order telencephalon, nidopallium caudolateral (NCL) were simultaneously recorded. LFPs of relay nuclei (the nucleus rotundus, ROT) of tectofugal pathway were also acquired. We demonstrated that LFP powers in the tectofugal pathway were higher than those in the thalamofugal pathway when illuminating blue lights. In addition, the LFP synchronization was stronger between the entopallium and NCL. LFPs also revealed a higher Granger causality from the direction of entopallium to NCL and from ROT to entopallium. These results suggest that zebra finches’ tectofugal pathway predominately processing color information from ROT to NCL, relayed by entopallium, and blue could trigger the strongest response.

Possible pathological mechanisms of absence seizures appearing in the reticular thalamic nucleus: A theoretical basis

In this paper, we study the generation and inhibition mechanisms of absence epilepsy appearing in the reticular thalamic nucleus (TRN) of the thalamus in a basal ganglia-corticothalamic network, which has been proven to be effective for simulating epileptic seizures in the brain. We found that the spike-and-wave discharges (SWDs) activities (2–4 Hz) appeared in the TRN by adjusting the coupling weight in the excitatory pathway “SRN ⟶ EPN” and the delay in the inhibitory pathway “TRN ⊸ Thalamic relay nucleus (SRN)”. The SWDs can disappear by controlling the firing state of the substantia nigra pars reticulata (SNr), which sends strong inhibitory projections to both the SRN and TRN in the model. Suppression of seizure activities may be realized through both the isolated pathway “SNr ⊸ TRN” and the isolated pathway “SNr ⊸ SRN”, or through the competition mechanism between them. Unidirectional and bidirectional regulation phenomena were obtained in the simulations, and the mechanisms of these can be well explained in this model. The theoretical mechanism of epilepsy appearing in the TRN has received little attention to date, and we hope that the results shown in this paper can inspire new ideas for experimental study in the future.

Olfaction in Lamprey Pallium Revisited – Roles of Mitral and Tufted Cells

The presence of two separate afferent channels from the olfactory glomeruli to different targets in the brain is unravelled in the lamprey. It represents the oldest group of now living vertebrates. The mitral cells send axonal projections directly to the piriform cortex in the ventral pallium, whereas the smaller tufted cells, identified here in the lamprey, project separately and exclusively to a relay nucleus called the dmtn. It is located at the interface between the olfactory bulb and pallium and in turn it projects to a circumscribed area in the anteromedial part of the ventral pallium. The tufted cells are activated with short latency and terminate with mossy fibres on the dmtn cells and elicit large unitary EPSPs. In all synapses along this tufted cell pathway there is no concurrent inhibition, in contrast to the mitral cell pathway. This is very similar to recent findings in rodents establishing two separate exclusive projection patterns, suggesting an evolutionary conserved organisation.

Improving control effects of absence seizures using single-pulse alternately resetting stimulation (SARS) of corticothalamic circuit

Presently, we develop a simplified corticothalamic (SCT) model and propose a single-pulse alternately resetting stimulation (SARS) with sequentially applying anodic (A, “+”) or cathodic (C, “−”) phase pulses to the thalamic reticular (RE) nuclei, thalamus-cortex (TC) relay nuclei, and cortical excitatory (EX) neurons, respectively. Abatement effects of ACC-SARS of RE, TC, and EX for the 2Hz–4Hz spike and wave discharges (SWD) of absence seizures are then concerned. The m:n on-off ACC-SARS protocol is shown to effectively reduce the SWD with the least current consumption. In particular, when its frequency is out of the 2 Hz–4Hz SWD dominant rhythm, the desired seizure abatements can be obtained, which can be further improved by our proposed directional steering (DS) stimulation. The dynamical explanations for the SARS induced seizure abatements are lastly given by calculating the averaged mean firing rate (AMFR) of neurons and triggering averaged mean firing rates (TAMFRs) of 2Hz–4Hz SWD.

Non-invasive High Frequency Repetitive Transcranial Magnetic Stimulation (hfrTMS) Robustly Activates Molecular Pathways Implicated in Neuronal Growth and Synaptic Plasticity in Select Populations of Neurons.

Patterns of neuronal activity that induce synaptic plasticity and memory storage activate kinase cascades in neurons that are thought to be part of the mechanism for synaptic modification. One such cascade involves induction of phosphorylation of ribosomal protein S6 in neurons due to synaptic activation of AKT/mTOR and via a different pathway, activation of MAP kinase/ERK1/2. Here, we show that phosphorylation of ribosomal protein S6 can also be strongly activated by high frequency repetitive transcranial magnetic stimulation (hfrTMS). HfrTMS was delivered to lightly anesthetized rats using a stimulation protocol that is a standard for inducing LTP in the perforant path in vivo (trains of 8 pulses at 400 Hz repeated at intervals of 1/10 s). Stimulation produced stimulus-locked motor responses but did not elicit behavioral seizures either during or after stimulation. After as little as 10 min of hfrTMS, immunostaining using phospho-specific antibodies for the phosphorylated form of ribosomal protein S6 (rpS6) revealed robust induction of rpS6 phosphorylation in large numbers of neurons in the cortex, especially the piriform cortex, and also in thalamic relay nuclei. Quantification revealed that the extent of the increased immunostaining depended on the number of trains and stimulus intensity. Of note, immunostaining for the immediate early genes Arc and c-fos revealed strong induction of IEG expression in many of the same populations of neurons throughout the cortex, but not the thalamus. These results indicate that hfrTMS can robustly activate molecular pathways critical for plasticity, which may contribute to the beneficial effects of TMS on recovery following brain and spinal cord injury and symptom amelioration in human psychiatric disorders. These molecular processes may be a useful surrogate marker to allow optimization of TMS parameters for maximal therapeutic benefit.

Afferent and efferent connections of the nucleus prethalamicus in the yellowfin goby Acanthogobius flavimanus.

The nucleus prethalamicus (PTh) receives fibers from the optic tectum and then projects to the dorsal telencephalon in the yellowfin goby Acanthogobius flavimanus. However, it remained unclear whether the PTh is a visual relay nucleus, because the optic tectum receives not only visual but also other sensory modalities. Furthermore, precise telencephalic regions receiving prethalamic input remained unknown in the goby. We therefore investigated the full set of afferent and efferent connections of the PTh by direct tracer injections into the nucleus. Injections into the PTh labeled cells in the optic tectum, ventromedial thalamic nucleus, central and medial parts of the dorsal telencephalon, and caudal lobe of the cerebellum. We found that the somata of most tecto-prethalamic neurons are present in the stratum periventriculare. Their dendrites ascend to reach the major retinorecipient layers of the tectum. The PTh is composed of two subnuclei (medial and lateral) and topographic organization was appreciated only for tectal projections to the lateral subnucleus (PTh-l), which also receives sparse retinal projections. In contrast, the medial subnucleus receives fibers only from the medial tectum. We found that the PTh projects to nine subregions in the dorsal telencephalon and four in the ventral telencephalon. Furthermore, cerebellar injections revealed that cerebello-prethalamic fibers cross the midline twice to innervate the PTh-l on both sides. The present study is the first detailed report on the full set of the connections of PTh, which suggests that the PTh relays visual information from the optic tectum to the telencephalon.

TRPM4 Conductances in Thalamic Reticular Nucleus Neurons Generate Persistent Firing during Slow Oscillations.

During sleep, neurons in the thalamic reticular nucleus (TRN) participate in distinct types of oscillatory activity. While the reciprocal synaptic circuits between TRN and sensory relay nuclei are known to underlie the generation of sleep spindles, the mechanisms regulating slow (<1 Hz) forms of thalamic oscillations are not well understood. Under in vitro conditions, TRN neurons can generate slow oscillations in a cell-intrinsic manner, with postsynaptic Group 1 metabotropic glutamate receptor activation triggering long-lasting plateau potentials thought to be mediated by both T-type Ca2+ currents and Ca2+-activated nonselective cation currents (ICAN). However, the identity of ICAN and the possible contribution of thalamic circuits to slow rhythmic activity remain unclear. Using thalamic slices derived from adult mice of either sex, we recorded slow forms of rhythmic activity in TRN neurons, which were driven by fast glutamatergic thalamoreticular inputs but did not require postsynaptic Group 1 metabotropic glutamate receptor activation. For a significant fraction of TRN neurons, synaptic inputs or brief depolarizing current steps led to long-lasting plateau potentials and persistent firing (PF), and in turn, resulted in sustained synaptic inhibition in postsynaptic relay neurons of the ventrobasal thalamus (VB). Pharmacological approachesindicated that plateau potentials were triggered by Ca2+ influx through T-type Ca2+ channels and mediated by Ca2+- and voltage-dependent transient receptor potential melastatin 4 (TRPM4) channels. Together, our results suggest that thalamic circuits can generate slow oscillatory activity, mediated by an interplay of TRN-VB synaptic circuits that generate rhythmicity and TRN cell-intrinsic mechanisms that control PF and oscillation frequency.SIGNIFICANCE STATEMENT Slow forms of thalamocortical rhythmic activity are thought to be essential for memory consolidation during sleep and the efficient removal of potentially toxic metabolites. In vivo, thalamic slow oscillations are regulated by strong bidirectional synaptic pathways linking neocortex and thalamus. Therefore, in vitro studies in the isolated thalamus offer important insights about the ability of individual neurons and local circuits to generate different forms of rhythmic activity. We found that circuits formed by GABAergic neurons in the thalamic reticular nucleus and glutamatergic relay neurons in the ventrobasal thalamus generated slow oscillatory activity, which was accompanied by persistent firing in thalamic reticular nucleus neurons. Our results identify both cell-intrinsic and synaptic mechanisms that mediate slow forms of rhythmic activity in thalamic circuits.

Modulating Motor Activity and White Matter Tracts Through Deep Brain Stimulation Surgery

Essential tremor (ET) is the world’s most common movement disorder and is more prevalent than Parkinson’s Disease and Epilepsy. Even though there is a high proportion of people with ET, recent evidence suggests that refined diagnostic criteria are needed to better classify or treat ET. Deep Brain Stimulation surgery (DBS) is a highly efficacious therapy for several movement disorders, including ET, that modulates pathologic brain activity in deep brain structures. Although DBS has been used to manage motor symptoms in ET, much remains unknown about how DBS activity in ET target affects down and upstream targets. The FDA approved DBS target for ET within a motor relay nucleus called the ventral intermediate nucleus of the thalamus (VIM). Within VIM, DBS stimulation parameters induce unique volume of tissue activation (VTA) within each patient. By quantifying VTA, clinicians can estimate the percent of VIM that is activated which could elucidate how the activity is spreading to other brain areas. The aim of the current study is twofold, to explore the localization of the VTA (1) within the area of VIM, and (2) use diffusion tensor imaging (DTI) tractography to trace white matter tracts transversing through the VTA to examine what cortical areas are being subsequently stimulated. Preliminary results (N = 11) from IRB approval number 16‐1060, were analyzed using MATLAB and LeadDBS. Calculating voxel data from co‐registered preoperative MRI and postoperative CT data indicates that the percent of VIM activated from VTA is on average 50.33%. DTI data has been collected and is actively being analyzed in MATLAB. This study will overlay brain maps formatted in MNI space to patient DTI data to map cortical areas activated by VTA. Future studies will examine how different electrode types affect and modify VTA, white matter tracts, and patient outcomes.

Types of Neurons in the Spinal Trigeminal Nucleus of the Camel Brain: Golgi Study

The camel lives in hot desert and eats thorny plants. It is exposed to severe environmental conditions such as dust, high temperature and thorny plants. These sensations from the face area may affect the development of neurons in the camel’s spinal trigeminal nucleus which contain the second‐order neurons of the sensory pathways for pain and temperature from the face area. Neurons in the spinal trigeminal nucleus of the camel were studied by Golgi impregnation.AimsThe aims of this study were to describe the different types of neurons in the spinal trigeminal nucleus and to compare these neurons with their counterparts in other species.MethodBlocks (2–4mm thick) of camel brainstem preserved in 10% formalin for months were cut and processed by two variations of Golgi Kopschi method (Fox and Braintenberg staining methods). Transverse sections (100 μm thick) were cut and examined under the light microscope. Well‐impregnated neurons were studied, measured and photographed.ResultsNeurons were classified based on differences in size and shape of their cell bodies, density of their dendritic trees, morphology and distribution of their appendages.In the spinal trigeminal nucleus of the camel, at least twelve types of neurons were identified. These neurons include, stalk, islets, octubus‐like, lobulated, boat‐like, pyramidal, multipolar, round, oval and elongated neurons. They have large number of different forms of appendages not only for their dendrites but also for their cell bodies. Neurons with unique large dilatations especially at their dendritic branching points were found. These neuronal types were found in the three divisions of the spinal trigeminal nucleus namely the spinal trigeminal caudalis, spinal trigeminal interpolaris and spinal trigeminal oralis. The morphological features of these neurons were described and compared with their counterparts in other species.ConclusionFinding of neurons with variation in number and shape, in addition, to variation in number and shape of the appendages on the cell bodies and dendrites may indicate the presence of a very complex information processing for pain and temperature at the level of the spinal trigeminal nucleus in the camel. Together with the presence of cells with unique features such as large dilated parts for dendrites, may suggest that, the spinal trigeminal nucleus in the camel serves as center for sensations processing and not only as relay nucleus for the pain and temperature pathways from the face. This study will improve our understanding of the function of the spinal trigeminal nucleus and contribute to our understanding of comparative neuroanatomy and neurophysiology.Support or Funding InformationResearch Grant 100/2011 from the Deanship of Scientific Research at Jordan University of Science and Technology

Alpha rhythm slowing in a modified thalamo-cortico-thalamic model related with Alzheimer's disease.

A decrease in alpha band power is defined as a hallmark of electroencephalogram (EEG) in Alzheimer’s disease (AD). This study devotes to understanding the neuronal correlates of alpha rhythm slowing associated with AD from the view of neurocomputation. Firstly, a modified computational model of thalamo-cortico-thalamic (TCT) circuitry is constructed by incorporating two important biologically plausible ingredients. One is the disinhibition property between different inhibitory interneurons in the cortical module. The other is the full relay function of thalamic relay nucleus (TCR) to the cortical module. Then, by decreasing synaptic connectivity parameters to mimic the neuropathological condition of synapse loss in AD, the correlation between neuronal synaptic behavior and abnormal alpha rhythm is simulated by means of power spectral analysis. The results indicate that these decreases of synaptic activity, i.e., not only the excitatory synaptic connections from TCR to fast inhibitory interneurons Cfte and from excitatory interneurons to pyramidal neurons Cpxe but also the inhibitory synaptic connections from fast inhibitory interneurons to slow inhibitory interneurons Clfi and from inhibitory interneurons to TCR Ctii, can significantly diminish the peak power density over the alpha band of the thalamic output, which implies that there is a slowing of alpha band. Furthermore, the underlying mechanism behind the alpha rhythmic changes is analyzed using nonlinear dynamical technique. The results reveal that decreases of Cfte, Cpxe, Clfi and Ctii can make the thalamic module transfer from a limit cycle mode to a point attractor mode, which may lead to the alpha rhythm slowing in the modified TCT model. We expect this work can be helpful in identifying early biomarkers of AD’s EEG and understanding potential pathogenesis of AD.

Organization of primate amygdalar-thalamic pathways for emotions.

Studies on the thalamus have mostly focused on sensory relay nuclei, but the organization of pathways associated with emotions is not well understood. We addressed this issue by testing the hypothesis that the primate amygdala acts, in part, like a sensory structure for the affective import of stimuli and conveys this information to the mediodorsal thalamic nucleus, magnocellular part (MDmc). We found that primate sensory cortices innervate amygdalar sites that project to the MDmc, which projects to the orbitofrontal cortex. As in sensory thalamic systems, large amygdalar terminals innervated excitatory relay and inhibitory neurons in the MDmc that facilitate faithful transmission to the cortex. The amygdala, however, uniquely innervated a few MDmc neurons by surrounding and isolating large segments of their proximal dendrites, as revealed by three-dimensional high-resolution reconstruction. Physiologic studies have shown that large axon terminals are found in pathways issued from motor systems that innervate other brain centers to help distinguish self-initiated from other movements. By analogy, the amygdalar pathway to the MDmc may convey signals forwarded to the orbitofrontal cortex to monitor and update the status of the environment in processes deranged in schizophrenia, resulting in attribution of thoughts and actions to external sources.

Individual Mesopontine Neurons Implicated in Anesthetic Loss-of-consciousness Employ Separate Ascending Pathways to the Cerebral Cortex

The mesopontine tegmental anesthesia area (MPTA) is a small brainstem nucleus that, when exposed to minute quantities of GABAA receptor agonists, induces a state of general anesthesia. In addition to immobility and analgesia this state is accompanied by widespread suppression of neural activity in the cerebral cortex and high delta-band power in the electroencephalogram. Collectively, MPTA neurons are known to project to a variety of forebrain targets which are known to relay to the cortex in a highly distributed manner. Here we ask whether ascending projections of individual MPTA neurons collateralize to several of these cortical relay nuclei, or access only one. Using rats, contrasting retrograde tracers were microinjected pairwise on one side into three ascending relays: the basal forebrain, the zona incerta-lateral hypothalamus and the intralaminar thalamic nuclear group. In addition, in separate animals, each target was microinjected bilaterally. MPTA neurons were then identified as being single-or double-labeled, indicating projection to one target nucleus or collateralization to both. Results indicated that double-labeling was rare, occurring on average in only 1.3% of the neurons sampled. The overwhelming majority of individual MPTA neurons showed specific connectivity, contributing to only one of the major ascending pathways, either ipsilaterally or contralaterally, but not bilaterally. This architecture would permit particular functional aspects of anesthetic loss-of-consciousness to be driven by specific subpopulations of MPTA neurons.

Early lesion of the reticular thalamic nucleus disrupts the structure and function of the mediodorsal thalamus and prefrontal cortex.

The thalamic reticular nucleus (TRN), part of the thalamus, is a thin GABAergic cell layer adjacent to the relay nuclei of the dorsal thalamus. It receives input from the cortex and other thalamic nuclei and provides major inhibitory input to each thalamic nucleus, particularly the mediodorsal nucleus (MD). As the MD is important for supporting optimal cortico-thalamo-cortical interactions during brain maturation, we hypothesized that that early damage to the TRN will cause major disturbances to the development and the functioning of the prefrontal cortex (PFC) and the MD. Rat pups at P4 were randomized in three groups: electrolytic lesion of TRN, TRN-sham-lesion group, and the classical control group. Seven weeks later, all rats were tested with several behavioral and cognitive paradigms, and then perfused for histological and immunohistochemical studies. Results showed that TRN lesion rats exhibited reduced spontaneous activity, high level of anxiety, learning and recognition memory impairments. Besides the behavioral effects observed after early TRN lesions, our study showed significant cytoarchitectural and functional changes in the cingulate cortex, the dorsolateral and prelimbic subdivisions of the PFC, as well as in the MD. The assessment of the basal levels of neuronal activity revealed a significant reduction of the basal expression of C-Fos levels in the PFC. These experiments, which are the first to highlight the effects of early TRN lesions, provided evidence that early damage of the anterior part of the TRN leads to alterations that may control the development of the thalamocortical-corticothalamic pathways.

Mechanisms and functional impact of Group I metabotropic glutamate receptor modulation of excitability in mouse MNTB neurons.

We examined effects of Group I metabotropic glutamate receptors on the excitability of mouse medial nucleus of the trapezoid body (MNTB) neurons. The selective agonist, S-3,5-dihydroxyphenylglycine (DHPG), evoked a dose-dependent depolarization of the resting potential, increased membrane resistance, increased sag depolarization, and promoted rebound action potential firing. Under voltage-clamp, DHPG evoked an inward current, referred to as IDHPG , which was developmentally stable through postnatal day P56. IDHPG had low temperature dependence in the range 25-34°C, consistent with a channel mechanism. However, the I-V relationship took the form of an inverted U that did not reverse at the calculated Nernst potential for K+ or Cl- . Thus, it is likely that more than one ion type contributes to IDHPG and the mix may be voltage dependent. IDHPG was resistant to the Na+ channel blockers tetrodotoxin and amiloride, and to inhibitors of iGluR (CNQX and MK801). IDHPG was inhibited 21% by Ba2+ (500μM), 60% by ZD7288 (100μM) and 73% when the two antagonists were applied together, suggesting that KIR channels and HCN channels contribute to the current. Voltage clamp measurements of IH indicated a small (6%) increase in Gmax by DHPG with no change in the voltage dependence. DHPG reduced action potential rheobase and reduced the number of post-synaptic AP failures during high frequency stimulation of the calyx of Held. Thus, activation of post-synaptic Group I mGlu receptors modifies the excitability of MNTB neurons and contributes to the reliability of high frequency firing in this auditory relay nucleus.

Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice

Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system having antiapoptotic effects. Expression of Ca2+-binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response (ABR) tests found higher hearing thresholds in KO mice at click and low frequency burst stimuli. Hearing impairment at higher frequencies showed as reduced ABR wave amplitudes and latencies in KO animals. Increase in neuronal activity, demonstrated by c-Fos immunolabeling, was lower in KO mice after noise exposure in the ventral and dorsal cochlear nuclei. Noise induced neuronal activation was similar in further relay nuclei of the auditory pathway of WT and KO mice. Based on the similar inflammatory and angiogenic protein profile data from cochlear duct lysates, neither inflammation nor disturbed angiogenesis, as potential pathological components in sensorineural hearing losses, seem to be involved in the pathomechanism of the presented functional and morphological changes in PACAP KO mice. The hearing impairment is probably concomitant with the markedly accelerated aging processes in these animals.

Synaptic connectivity of urinary bladder afferents in the rat superficial dorsal horn and spinal parasympathetic nucleus.

That visceral sensory afferents are functionally distinct from their somatic analogues has been known for a long time but the detailed knowledge of their synaptic connections and neurotransmitters at the first relay nucleus in the spinal cord has been limited. To provide information on these topics, we investigated the synapses and neurotransmitters of identified afferents from the urinary bladder to the superficial laminae of the rat spinal dorsal horn (DH) and the spinal parasympathetic nucleus (SPN) by tracing with horseradish peroxidase, quantitative electron microscopical analysis, and immunogold staining for GABA and glycine. In the DH, most bladder afferent boutons formed synapses with 1-2 postsynaptic dendrites, whereas in the SPN, close to a half of them formed synapses with 3-8 postsynaptic dendrites. The number of postsynaptic dendrites and dendritic spines per bladder afferent bouton, both measures of synaptic divergence and of potential for synaptic plasticity at a single bouton level, were significantly higher in the SPN than in the DH. Bladder afferent boutons frequently received inhibitory axoaxonic synapses from presynaptic endings in the DH but rarely in the SPN. The presynaptic endings were GABA- and/or glycine-immunopositive. The bouton volume, mitochondrial volume, and active zone area, all determinants of synaptic strength, of the bladder afferent boutons were positively correlated with the number of postsynaptic dendrites. These findings suggest that visceral sensory information conveyed via the urinary bladder afferents is processed differently in the DH than in the SPN, and differently from the way somatosensory information is processed in the spinal cord.

Neuroscience: Figured Out by Feedback to the Thalamus

The lateral geniculate nucleus of the thalamus (LGN) is a relay nucleus between the retina and the visual cortex. A new brain imaging study shows that LGN activity is modulated by figure-ground organization, even when the figure and ground are presented to different eyes: a hallmark of a cortical feedback effect.

Mouse BOLD fMRI at ultrahigh field detects somatosensory networks including thalamic nuclei

Forepaw somatosensory stimulation induces neural activities in relay thalamic nuclei, the primary somatosensory cortex of forelimb (S1FL), and the secondary somatosensory cortex (S2). However, rodent fMRI studies of somatosensory stimulation have commonly reported BOLD changes only in S1FL, which may be due to side effects of anesthetics and/or the low sensitivity in the thalamus. Thus, we have obtained mouse BOLD fMRI under newly-adopted ketamine-xylazine anesthesia. High-resolution BOLD fMRI obtained with same imaging parameters at 9.4T versus 15.2T shows the improvement of functional detectability by ≥ 2 times at 15.2T due to higher signal intensity and larger BOLD response. The fMRI responses at 15.2T were robustly observed at well-known somatosensory networks including thalamus. Second, echo-time-dependent BOLD signals are dominant based on multi-echo fMRI data. A ratio of BOLD responses in S1FL to thalamus is ∼2, which is not related to different baseline T2∗ or different cerebral blood volume. Third, group-averaged 15.2T BOLD maps show activities in S1FL, S2, motor cortices, and thalamic nuclei, which agree well with neural tracing network data from the Allen Institute, demonstrating that fMRI detects entire somatosensory networks. Our data suggest that ultrahigh field fMRI provides a unique window into understanding functional networks in normal and transgenic mouse models noninvasively.

Cell‐type specific expression of GluN2C and GluN2D subunits and their role in schizophrenic phenotypes

IntroductionFunctional deficit in NMDA‐receptors on parvalbumin (PV)‐positive interneurons (PV‐NMDARs) is central to the pathophysiology of schizophrenia. NMDA channel blockers like ketamine and MK‐801 have shown to produce psychosis by inhibiting GluN2C and GluN2D subunits with greater affinity than other subunits. Recent neuroanatomical and electrophysiological studies have reported expression of GluN2D subunit in PV positive interneurons in corticolimbic regions but the precise distribution of GluN2C subunit especially in PV interneurons remains unknown.Hence, the objective of the study was to identify the expression pattern of GluN2C subunit in neuronal and non‐neuronal cell population and to perform a side‐by‐side comparison of the effect of partial and complete ablation of GluN2C and GluN2D subunit on pure C57BL/6N mouse strain.Methods and ResultsImmunohistochemistry was used to determine the heterogenous expression of GluN2C using a novel eGFP reporter mouse model. We found the expression of EGFP (GluN2C) with PV positive neurons in nucleus reticularis of the thalamus, globus pallidus externa and interna, ventral pallidum and substantia nigra. Interestingly, EGFP (GluN2C) showed co‐localization with astrocytic marker in the striatum, cortex, hippocampus and amygdala but not with PV positive neurons. GluN2C was found to be enriched in several thalamic relay nuclei including first order and higher order nuclei. GluN2D knockout mouse exhibited hypo‐locomotion and anxiety‐like behavior in the open field test. We found a significant increase in startle amplitude in GluN2C HET but not GluN2C KO and no change in prepulse inhibition (PPI) in either genotype was observed. Increase in startle response was found for GluN2D heterozygous and GluN2D knockout along with lower prepulse inhibition at some decibels. We also found CIQ, a selective positive allosteric modulator for GluN2C/GluN2D subunit, reversed the MK801 induced impairment in PPI in GluN2C wildtype and heterozygous mice but not in GluN2C KO mice. Furthermore, we observed that GluN2C knockout mice but not GluN2D knockout mice were less sensitive to phencyclidine‐induced hyperlocomotion, a model of psychosis. The cell‐type specific expression of both GluN2C and GluN2D subunit may provide more insights into schizophrenia‐like behaviors. Hence, we will confirm psychotic and sensorimotor deficits by selectively deleting GluN2D subunit from PV‐positive interneurons and GluN2C subunit from astrocytes using Cre‐lox strategy.ConclusionTogether, these results identify the unique expression pattern of GluN2C subunit in neuronal and non‐neuronal cell population. It also demonstrates the preferential involvement of GluN2C‐ containing receptors in phencyclidine‐induced hyperlocomotion and that facilitation of GluN2C subunit may reverse the schizophrenic phenotypes.Support or Funding InformationR21 NS104705This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Stimulation strategies for absence seizures: targeted therapy of the focus in coupled thalamocortical model

Motivated by the recent experimental findings that thalamic reticular nucleus (TRN) may be a pacemaker of absence seizures, we explore whether changes in the level of TRN activation can induce absence seizures by using a coupled thalamocortical model. We first simulate different firing states by considering the interaction of pathway between cortical excitatory pyramidal neuronal population (PY)–TRN and specific relay nucleus (SRN)–TRN. By simultaneously increasing the coupling strength of each of these pathways, we can reproduce the absence seizures, which indicates that epileptic seizures may be caused by activating the TRN. We further infer that the TRN may be an epileptogenic focus. Following this, different stimulation strategies, including deep brain stimulation, 1:0 coordinated reset stimulation (CRS) and 3:2 CRS, are applied in TRN. By qualitatively analyzing the efficacy of three different stimulation methods, we find that 3:2 CRS is a more effective and safe method to control absence seizures in the first compartment, for which we then further explore the impact of 3:2 CRS in the second compartment. The results show that the additional stimulation in the second compartment also can lead to a considerable decrease in the spike-and-wave discharges (SWD) oscillation region. Therefore, we conclude that TRN-3:2 CRS is an optimal electrical stimulation method for our modeling and simulation studies. Furthermore, we hope that these numerical simulation results can provide some references for the treatment of real epilepsy patients in the future.