Opponent Learning with Different Representations in the Cortico-Basal Ganglia Circuits.

The direct and indirect pathways of the basal ganglia (BG) have been suggested to learn mainly from positive and negative feedbacks, respectively. Since these pathways unevenly receive inputs from different cortical neuron types and/or regions, they may preferentially use different state/action representations. We explored whether such a combined use of different representations, coupled with different learning rates from positive and negative reward prediction errors (RPEs), has computational benefits. We modeled animal as an agent equipped with two learning systems, each of which adopted individual representation (IR) or successor representation (SR) of states. With varying the combination of IR or SR and also the learning rates from positive and negative RPEs in each system, we examined how the agent performed in a dynamic reward navigation task. We found that combination of SR-based system learning mainly from positive RPEs and IR-based system learning mainly from negative RPEs could achieve a good performance in the task, as compared with other combinations. In such a combination of appetitive SR-based and aversive IR-based systems, both systems show activities of comparable magnitudes with opposite signs, consistent with the suggested profiles of the two BG pathways. Moreover, the architecture of such a combination provides a novel coherent explanation for the functional significance and underlying mechanism of diverse findings about the cortico-BG circuits. These results suggest that particularly combining different representations with appetitive and aversive learning could be an effective learning strategy in certain dynamic environments, and it might actually be implemented in the cortico-BG circuits.

Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior.

Dysfunctional dopamine signaling is implicated in various neuropsychological disorders. Previously, we reported that dopamine increases D1 receptor (D1R)-expressing medium spiny neuron (MSN) excitability and firing rates in the nucleus accumbens (NAc) via the PKA/Rap1/ERK pathway to promote reward behavior. Here, the results show that the D1R agonist, SKF81297, inhibits KCNQ-mediated currents and increases D1R-MSN firing rates in murine NAc slices, which is abolished by ERK inhibition. In vitro ERK phosphorylates KCNQ2 at Ser414 and Ser476; in vivo, KCNQ2 is phosphorylated downstream of dopamine signaling in NAc slices. Conditional deletion of Kcnq2 in D1R-MSNs reduces the inhibitory effect of SKF81297 on KCNQ channel activity, while enhancing neuronal excitability and cocaine-induced reward behavior. These effects are restored by wild-type, but not phospho-deficient KCNQ2. Hence, D1R-ERK signaling controls MSN excitability via KCNQ2 phosphorylation to regulate reward behavior, making KCNQ2 a potential therapeutical target for psychiatric diseases with a dysfunctional reward circuit.

Presynaptic supervision of cortical spine dynamics in motor learning.

In mammalian neocortex, learning triggers the formation and turnover of new postsynaptic spines on pyramidal cell dendrites. However, the biological principles of spine reorganization during learning remain elusive because the identity of their presynaptic neuronal partners is unknown. Here, we show that two presynaptic neural circuits supervise distinct programs of spine dynamics to execute learning. We imaged spine dynamics in motor cortex during learning and performed post hoc identification of their afferent presynaptic neurons. New spines that appeared during learning formed small transient contacts with corticocortical neurons that were eliminated on skill acquisition. In contrast, persistent spines with axons from thalamic neurons were formed and enlarged. These results suggest that pyramidal cell dendrites in motor cortex use a neural circuit division of labor during skill learning, with dynamic teaching contacts from top-down intracortical axons followed by synaptic memory formation driven by thalamic axons. Dual spine supervision may govern diverse skill learning in the neocortex.

Corticocortical innervation subtypes of layer 5 intratelencephalic cells in the murine secondary motor cortex.

Feedback projections from the secondary motor cortex (M2) to the primary motor and sensory cortices are essential for behavior selection and sensory perception. Intratelencephalic (IT) cells in layer 5 (L5) contribute feedback projections to diverse cortical areas. Here we show that L5 IT cells participating in feedback connections to layer 1 (L1) exhibit distinct projection patterns, genetic profiles, and electrophysiological properties relative to other L5 IT cells. An analysis of the MouseLight database found that L5 IT cells preferentially targeting L1 project broadly to more cortical regions, including the perirhinal and auditory cortices, and innervate a larger volume of striatum than the other L5 IT cells. We found experimentally that in upper L5 (L5a), ER81 (ETV1) was found more often in L1-preferring IT cells, and in IT cells projecting to perirhinal/auditory regions than those projecting to primary motor or somatosensory regions. The perirhinal region-projecting L5a IT cells were synaptically connected to each other and displayed lower input resistance than contra-M2 projecting IT cells including L1-preferring and nonpreferring cells. Our findings suggest that M2-L5a IT L1-preferring cells exhibit stronger ER81 expression and broader cortical/striatal projection fields than do cells that do not preferentially target L1.

Pyramidal cell subtype-dependent cortical oscillatory activity regulates motor learning.

The cortex processes information through intricate circuitry and outputs to multiple brain areas by different sets of pyramidal cells (PCs). PCs form intra- and inter-laminar subnetworks, depending on PC projection subtypes. However, it remains unknown how individual PC subtypes are involved in cortical network activity and, thereby, in distinct brain functions. Here, we examined the effects of optogenetic manipulations of specific PC subtypes on network activity in the motor cortex. In layer V, the beta/gamma frequency band of oscillation was evoked by photostimulation, depending on PC subtypes. Our experimental and simulation results suggest that oscillatory activity is generated in reciprocal connections between pyramidal tract (PT) and fast-spiking cells. A similar frequency band was also observed in local field potentials during a pattern learning task. Manipulation of PT cell activity affected beta/gamma band power and learning. Our results suggest that PT cell-dependent oscillations play important roles in motor learning.

Differential Striatal Axonal Arborizations of the Intratelencephalic and Pyramidal-Tract Neurons: Analysis of the Data in the MouseLight Database.

There exist two major types of striatum-targeting neocortical neurons, specifically, intratelencephalic (IT) neurons and pyramidal-tract (PT) neurons. Regarding their striatal projections, it was once suggested that IT axons are extended whereas PT axons are primarily focal. However, subsequent study with an increased number of well-stained extended axons concluded that such an apparent distinction was spurious due to limited sample size. Recent work using genetically labeled neurons reintroduced the differential spatial extent of the striatal projections of IT and PT neurons through population-level analyses, complemented by observations of single axons. However, quantitative IT vs. PT comparison of a large number of axons remained to be conducted. We analyzed the data of axonal end-points of 161 IT neurons and 33 PT neurons in the MouseLight database (http://ml-neuronbrowser.janelia.org/). The number of axonal end-points in the ipsilateral striatum exhibits roughly monotonically decreasing distributions in both neuron types. Excluding neurons with no ipsilateral end-point, the distributions of the logarithm of the number of ipsilateral end-points are considerably overlapped between IT and PT neurons, although the proportion of neurons having more than 50 ipsilateral end-points is somewhat larger in IT neurons than in PT neurons. Looking at more details, among IT subpopulations in the secondary motor area (MOs), layer 5 neurons and bilateral striatum-targeting layer 2/3 neurons, but not contralateral striatum-non-targeting layer 2/3 neurons, have a larger number of ipsilateral end-points than MOs PT neurons. We also found that IT ipsilateral striatal axonal end-points are on average more widely distributed than PT end-points, especially in the medial-lateral direction. These results indicate that IT and PT striatal axons differ in the frequencies and spatial extent of end-points while there are wide varieties within each neuron type.

Semaphorin 6A-Plexin A2/A4 Interactions with Radial Glia Regulate Migration Termination of Superficial Layer Cortical Neurons.

Precise regulation of neuronal migration termination is crucial for the establishment of brain cytoarchitectures. However, little is known about how neurons terminate migration. Here we focused on interactions between migrating cortical neurons and their substrates, radial glial (RG) cells, and analyzed the role of Plexin A2 and A4 (PlxnA2/A4) receptors and their repulsive ligand, Semaphorin 6A (Sema6A), for this process. In both PlxnA2/A4 double-knockout and Sema6A mutant mice, the outermost cortical plate neurons ectopically invade layer 1 at a stage when they should reach their destinations. PlxnA2/A4 proteins are abundantly expressed on their leading processes, whereas Sema6A mRNA is enriched in RG cell somata. Cell-targeted gene expression and conditional knockouts indicate critical roles for these molecules. We hypothesize that the timely appearance of repulsive signaling mediated by Sema6A-PlxnA2/A4 weakens migrating neuron-RG cell interactions, leading to migration termination.

Ipsi- and contralateral corticocortical projection-dependent subcircuits in layer 2 of the rat frontal cortex.

In the neocortex, both layer 2/3 and layer 5 contain corticocortical pyramidal cells projecting to other cortices. We previously found that among L5 pyramidal cells of the secondary motor cortex (M2), not only intratelencephalic projection cells but also pyramidal tract cells innervate ipsilateral cortices and that the two subtypes are different in corticocortical projection diversity and axonal laminar distributions. Layer 2/3 houses intratelencephalically projecting pyramidal cells that also innervate multiple ipsilateral and contralateral cortices. However, it remained unclear whether layer 2/3 pyramidal cells can be divided into projection subtypes each with distinct innervation to specific targets. In the present study we show that layer 2 pyramidal cells are organized into subcircuits on the basis of corticocortical projection targets. Layer 2 corticocortical cells of the same projection subtype were monosynaptically connected. Between the contralaterally and ipsilaterally projecting corticocortical cells, the monosynaptic connection was more common from the former to the latter. We also found that ipsilaterally and contralaterally projecting corticocortical cell subtypes differed in their morphological and physiological characteristics. Our results suggest that layer 2 transfers separate outputs from M2 to individual cortices and that its subcircuits are hierarchically organized to form the discrete corticocortical outputs.NEW & NOTEWORTHY Pyramidal cell subtypes and their dependent subcircuits are well characterized in cortical layer 5, but much less is understood for layer 2/3. We demonstrate that in layer 2 of the rat secondary motor cortex, ipsilaterally and contralaterally projecting corticocortical cells are largely segregated. These layer 2 cell subtypes differ in dendrite morphological and intrinsic electrophysiological properties, and form subtype-dependent connections. Our results suggest that layer 2 pyramidal cells form distinct subcircuits to provide discrete corticocortical outputs.

Control of excitatory hierarchical circuits by parvalbumin-FS basket cells in layer 5 of the frontal cortex: insights for cortical oscillations.

The cortex contains multiple neuron types with specific connectivity and functions. Recent progress has provided a better understanding of the interactions of these neuron types as well as their output organization particularly for the frontal cortex, with implications for the circuit mechanisms underlying cortical oscillations that have cognitive functions. Layer 5 pyramidal cells (PCs) in the frontal cortex comprise two major subtypes: crossed-corticostriatal (CCS) and corticopontine (CPn) cells. Functionally, CCS and CPn cells exhibit similar phase-dependent firing during gamma waves but participate in two distinct subnetworks that are linked unidirectionally from CCS to CPn cells. GABAergic parvalbumin-expressing fast-spiking (PV-FS) cells, necessary for gamma oscillation, innervate PCs, with stronger and global inhibition to somata and weaker and localized inhibitions to dendritic shafts/spines. While PV-FS cells form reciprocal connections with both CCS and CPn cells, the excitation from CPn to PV-FS cells exhibits short-term synaptic dynamics conducive for oscillation induction. The electrical coupling between PV-FS cells facilitates spike synchronization among PV-FS cells receiving common excitatory inputs from local PCs and inhibits other PV-FS cells via electrically communicated spike afterhyperpolarizations. These connectivity characteristics can promote synchronous firing in the local networks of CPn cells and firing of some CCS cells by anode-break excitation. Thus subsets of L5 CCS and CPn cells within different levels of connection hierarchy exhibit coordinated activity via their common connections with PV-FS cells, and the resulting PC output drives diverse neuronal targets in cortical layer 1 and the striatum with specific temporal precision, expanding the computational power of the cortical network.

Large Volume Electron Microscopy and Neural Microcircuit Analysis.

One recent technical innovation in neuroscience is microcircuit analysis using three-dimensional reconstructions of neural elements with a large volume Electron microscopy (EM) data set. Large-scale data sets are acquired with newly-developed electron microscope systems such as automated tape-collecting ultramicrotomy (ATUM) with scanning EM (SEM), serial block-face EM (SBEM) and focused ion beam-SEM (FIB-SEM). Currently, projects are also underway to develop computer applications for the registration and segmentation of the serially-captured electron micrographs that are suitable for analyzing large volume EM data sets thoroughly and efficiently. The analysis of large volume data sets can bring innovative research results. These recently available techniques promote our understanding of the functional architecture of the brain.

Thalamocortical Axonal Activity in Motor Cortex Exhibits Layer-Specific Dynamics during Motor Learning.

The thalamus is the hub through which neural signals are transmitted from the basal ganglia and cerebellum to the neocortex. However, thalamocortical axonal activity during motor learning remains largely undescribed. We conducted two-photon calcium imaging of thalamocortical axonal activity in the motor cortex of mice learning a self-initiated lever-pull task. Layer 1 (L1) axons came to exhibit activity at lever-pull initiation and termination, while layer 3 (L3) axons did so at lever-pull initiation. L1 population activity had a sequence structure related to both lever-pull duration and reproducibility. Stimulation of the substantia nigra pars reticulata activated more L1 than L3 axons, whereas deep cerebellar nuclei (DCN) stimulation did the opposite. Lesions to either the dorsal striatum or the DCN impaired motor learning and disrupted temporal dynamics in both layers. Thus, layer-specific thalamocortical signals evolve with the progression of learning, which requires both the basal ganglia and cerebellar activities.

Afferent loop obstruction with obstructive jaundice and ileus due to an enterolith after distal gastrectomy: A case report.

INTRODUCTION: Afferent loop obstruction is an uncommon complication associated with Billroth II reconstruction or Roux-en-Y reconstruction after gastrectomy. Moreover, cases where the obstruction is caused by enterolith are rare. Here, we report a rare case of afferent loop obstruction caused by an enterolith after Roux-en-Y reconstruction of gastrectomy; subsequently, leading to ileus in the ileum. PRESENTATION OF CASE: An 84-year-old man who received a Roux-en-Y distal gastrectomy for gastric cancer presented with symptoms of fever and jaundice 14 months later. Computed tomography (CT) scan revealed an enterolith in the duodenal afferent loop and a dilated intrahepatic bile duct. Although the obstructive jaundice and fever disappeared with conservative therapy, ileus occurred due to the movement of the enterolith into the ileum, which was refractory to conservative therapy. Therefore, enterotomy was performed to remove the enterolith, and the patient had an uneventful recovery. Histologically, the enterolith derived from food residue. No postsurgical sign of recurrence has been noted for 6 months. CONCLUSION: We report a rare case where an enterolith in a duodenal afferent loop after distal gastrectomy led to obstructive jaundice, and subsequently, caused ileus by its movement into the ileum.

Monitoring and Updating of Action Selection for Goal-Directed Behavior through the Striatal Direct and Indirect Pathways.

The basal ganglia play key roles in adaptive behaviors guided by reward and punishment. However, despite accumulating knowledge, few studies have tested how heterogeneous signals in the basal ganglia are organized and coordinated for goal-directed behavior. In this study, we investigated neuronal signals of the direct and indirect pathways of the basal ganglia as rats performed a lever push/pull task for a probabilistic reward. In the dorsomedial striatum, we found that optogenetically and electrophysiologically identified direct pathway neurons encoded reward outcomes, whereas indirect pathway neurons encoded no-reward outcome and next-action selection. Outcome coding occurred in association with the chosen action. In support of pathway-specific neuronal coding, light activation induced a bias on repeat selection of the same action in the direct pathway, but on switch selection in the indirect pathway. Our data reveal the mechanisms underlying monitoring and updating of action selection for goal-directed behavior through basal ganglia circuits.

A carbon nanotube tape for serial-section electron microscopy of brain ultrastructure.

Automated tape-collecting ultramicrotomy in conjunction with scanning electron microscopy (SEM) is a powerful approach for volume electron microscopy and three-dimensional neuronal circuit analysis. Current tapes are limited by section wrinkle formation, surface scratches and sample charging during imaging. Here we show that a plasma-hydrophilized carbon nanotube (CNT)-coated polyethylene terephthalate (PET) tape effectively resolves these issues and produces SEM images of comparable quality to those from transmission electron microscopy. CNT tape can withstand multiple rounds of imaging, offer low surface resistance across the entire tape length and generate no wrinkles during the collection of ultrathin sections. When combined with an enhanced en bloc staining protocol, CNT tape-processed brain sections reveal detailed synaptic ultrastructure. In addition, CNT tape is compatible with post-embedding immunostaining for light and electron microscopy. We conclude that CNT tape can enable high-resolution volume electron microscopy for brain ultrastructure analysis.

Sessile serrated adenoma/polyp leading to acute appendicitis with multiple pyogenic liver abscesses: A case report.

INTRODUCTION: Although appendicitis is a common disease, appendicitis concurrent with liver abscesses and sessile serrated adenoma/polyp (SSA/P) is rare. PRESENTATION OF CASE: A 69-year-old man presented with symptoms of abdominal pain and fever. Computed tomography (CT) revealed multiple liver abscesses and an enlarged appendix with a pseudotumoral appearance, which suggested acute appendicitis. In the emergency operation, ileocecal resection was performed for the perforated appendicitis with an inflammatory mass in the ileocecum. On macroscopic examination, the torose lesion was localized at next to the appendiceal orifice. The tumor was diagnosed as SSA/P based on the microscopic finding. The postoperative course was uneventful, and the liver abscesses were cured by antibiotic therapy. The patient was discharged 17days after the surgery. DISCUSSION: In this case, SSA/P localization at next to the appendiceal orifice was suggested as the cause of the perforated appendicitis with multiple liver abscesses. The patient was successfully treated with a combination of surgery and antibiotic therapy. CONCLUSION: This is the first reported case of a patient with SSA/P that led to acute appendicitis with multiple pyogenic liver abscesses.

A Dual Role Hypothesis of the Cortico-Basal-Ganglia Pathways: Opponency and Temporal Difference Through Dopamine and Adenosine.

The hypothesis that the basal-ganglia direct and indirect pathways represent goodness (or benefit) and badness (or cost) of options, respectively, explains a wide range of phenomena. However, this hypothesis, named the Opponent Actor Learning (OpAL), still has limitations. Structurally, the OpAL model does not incorporate differentiation of the two types of cortical inputs to the basal-ganglia pathways received from intratelencephalic (IT) and pyramidal-tract (PT) neurons. Functionally, the OpAL model does not describe the temporal-difference (TD)-type reward-prediction-error (RPE), nor explains how RPE is calculated in the circuitry connecting to the DA neurons. In fact, there is a different hypothesis on the basal-ganglia pathways and DA, named the Cortico-Striatal-Temporal-Difference (CS-TD) model. The CS-TD model differentiates the IT and PT inputs, describes the TD-type RPE, and explains how TD-RPE is calculated. However, a critical difficulty in this model lies in its assumption that DA induces the same direction of plasticity in both direct and indirect pathways, which apparently contradicts the experimentally observed opposite effects of DA on these pathways. Here, we propose a new hypothesis that integrates the OpAL and CS-TD models. Specifically, we propose that the IT-basal-ganglia pathways represent goodness/badness of current options while the PT-indirect pathway represents the overall value of the previously chosen option, and both of these have influence on the DA neurons, through the basal-ganglia output, so that a variant of TD-RPE is calculated. A key assumption is that opposite directions of plasticity are induced upon phasic activation of DA neurons in the IT-indirect pathway and PT-indirect pathway because of different profiles of IT and PT inputs. Specifically, at PT→indirect-pathway-medium-spiny-neuron (iMSN) synapses, sustained glutamatergic inputs generate rich adenosine, which allosterically prevents DA-D2 receptor signaling and instead favors adenosine-A2A receptor signaling. Then, phasic DA-induced phasic adenosine, which reflects TD-RPE, causes long-term synaptic potentiation. In contrast, at IT→iMSN synapses where adenosine is scarce, phasic DA causes long-term synaptic depression via D2 receptor signaling. This new Opponency and Temporal-Difference (OTD) model provides unique predictions, part of which is potentially in line with recently reported activity patterns of neurons in the globus pallidus externus on the indirect pathway.

Segregated Excitatory-Inhibitory Recurrent Subnetworks in Layer 5 of the Rat Frontal Cortex.

A prominent feature of neocortical pyramidal cells (PCs) is their numerous projections to diverse brain areas. In layer 5 (L5) of the rat frontal cortex, there are 2 major subtypes of PCs that differ in their long-range axonal projections, corticopontine (CPn) cells and crossed corticostriatal (CCS) cells. The outputs of these L5 PCs can be regulated by feedback inhibition from neighboring cortical GABAergic cells. Two major subtypes of GABAergic cells are parvalbumin (PV)-positive and somatostatin (SOM)-positive cells. PV cells have a fast-spiking (FS) firing pattern, while SOM cells have a low threshold spike (LTS) and regular spiking. In this study, we found that the 2 PC subtypes in L5 selectively make recurrent connections with LTS cells. The connection patterns correlated with the morphological and physiological diversity of LTS cells. LTS cells with high input resistance (Ri) exhibited more compact dendrites and more rebound spikes than LTS cells with low Ri, which had vertically elongated dendrites. LTS subgroups differently inhibited the PC subtypes, although FS cells made nonselective connections with both projection subtypes. These results demonstrate a novel recurrent network of inhibitory and projection-specific excitatory neurons within the neocortex.

Pyramidal Cell Subtypes and Their Synaptic Connections in Layer 5 of Rat Frontal Cortex.

The frontal cortical areas make a coordinated response that generates appropriate behavior commands, using individual local circuits with corticostriatal and corticocortical connections in longer time scales than sensory areas. In secondary motor cortex (M2), situated between the prefrontal and primary motor areas, major subtypes of layer 5 corticostriatal cells are crossed-corticostriatal (CCS) cells innervating both sides of striatum, and corticopontine (CPn) cells projecting to the ipsilateral striatum and pontine nuclei. CCS cells innervate CPn cells unidirectionally: the former are therefore hierarchically higher than the latter among L5 corticostriatal cells. CCS cells project directly to both frontal and nonfrontal areas. On the other hand, CPn cells innervate the thalamus and layer 1a of frontal areas, where thalamic fibers relaying basal ganglia outputs are distributed. Thus, CCS cells can make activities of frontal areas in concert with those of nonfrontal area using corticocortical loops, whereas CPn cells are more involved in closed corticostriatal loops than CCS cells. Since reciprocal connections between CPn cells with facilitatory synapses may be related to persistent activity, CPn cells play a key role of longer time constant processes in corticostriatal as well as in corticocortical loops between the frontal areas.

De Garengeot hernia with perforated appendicitis and a groin subcutaneous abscess: A case report.

INTRODUCTION: De Garengeot hernia is rare. Although previous reports have suggested various surgical options according to patient condition, comorbidities, surgeon preference, and clinical findings during surgery, a treatment strategy has not been established. PRESENTATION OF CASE: An 81-year-old woman presented with an irreducible tender mass that was subsequently diagnosed as an incarcerated femoral hernia with a subcutaneous abscess in the right groin. Intraoperative findings revealed a necrotic and perforated appendix strangulated by the femoral ring for which an appendectomy and herniorrhaphy was performed concurrently through the hernia sac. The subcutaneous abscess cavity was washed thoroughly and a drainage tube was placed within it. The patient recovered uneventfully. DISCUSSION: We suggest that the approach through the inguinal incision in both appendectomy and herniorrhaphy with drainage may be useful in avoiding intra-abdominal contamination in cases of de Garengeot hernia with subcutaneous abscess. CONCLUSION: Here, we described a case of de Garengeot hernia with a subcutaneous abscess in the groin. Clinicians should consider de Garengeot hernia in patients with a groin hernia, make an early diagnosis, and promptly provide surgical treatment to reduce the risk of complications.