[Learning and Neural Activity: Beyond Localization].

Learning is classified into two types: "classical conditioning," which modifies simple reflexes, and "operant conditioning," which modifies complex voluntary behaviors. The neural circuits underlying these two types differ significantly. During the learning process of operant conditioning tasks, various changes in firing rate and firing synchrony of neurons can be observed across multiple brain regions. Additionally, neuronal firing rate and synchrony in several brain regions can be voluntarily controlled through operant conditioning. Consequently, it is evident that neurons in widespread brain regions have the potential for plastic changes to facilitate learning. It may be suggested that the learning of complex voluntary behaviors is underlined by widespread dynamic changes in neural activity and is not restricted to only a few brain regions.

An intra-oral flavor detection task in freely moving mice.

Flavor plays a critical role in the pleasure of food. Flavor research has mainly focused on human subjects and revealed that many brain regions are involved in flavor perception. However, animal models for elucidating the mechanisms of neural circuits are lacking. Herein, we demonstrate the use of a novel behavioral task in which mice are capable of flavor detection. When the olfactory pathways of the mice were blocked, they could not perform the task. However, behavioral accuracy was not affected when the gustatory pathway was blocked by benzocaine. These results indicate that the mice performed this detection task mainly based on the olfaction. We conclude that this novel task can contribute to research on the neural mechanisms of flavor perception.

Rats adaptively seek information to accommodate a lack of information.

Metacognition is the ability to adaptively control one's behavior by referring to one's own cognitive processes. It is thought to contribute to learning in situations where there is insufficient information available from the environment. Information-seeking behavior is a type of metacognition in which one confirms the necessary information only when one does not have the necessary and sufficient information to accomplish a task. The rats were required to respond to a nose poke hole on one wall of the experimental box for a certain period of time and then move to the opposite side at a specific time. Unfortunately, they were unable to match the timing when responding to the hole on one side. Therefore, they had to look back and confirm that now was the right time. The results obtained by analyzing these looking-back movements using a motion capture system showed that this behavior occurred frequently and rapidly in situations of insufficient information, such as in the early stages of learning, but was hardly observed and became slower as learning progressed. These results suggest that rats can adjust their behavior in response to a lack of information more flexibly than previously assumed.

Efficacy of cEEG and hepatic function to diagnose early acute encephalopathy.

BACKGROUND: Early treatment may improve the prognosis of acute encephalopathy (AE). However, methods for early diagnosis have not yet been established. In this paper, we examined methods for the early diagnosis of AE. METHODS: We extracted data on patients with febrile status epilepticus from the electronic medical records in our department between March 2016 and April 2021. Among these, 79 patients who underwent continuous electroencephalography (cEEG) were included in this study. Patients who exhibited psychomotor retardation or abnormal brain magnetic resonance imaging findings were assigned to Group E (n = 20), and the remaining patients were the control group (Group C, n = 59). The following tests were compared retrospectively between these two groups on admission: cEEG, serum hepatic function tests, and blood coagulation tests. RESULTS: The percentage of patients who exhibited high-amplitude slow waves or flat waves on cEEG at the time of admission was statistically significantly higher in Group E than in Group C (p < 0.01). Moreover, the percentage of patients whose high-amplitude slow waves or flat brain waves on admission disappeared within 6 h after an initial episode of convulsion was statistically significantly lower in Group E than in Group C (p < 0.01). Furthermore, all the items in the coagulation and the hepatic function tests were statistically significantly different in Group E from those in Group C (p < 0.05). CONCLUSION: These results showed that cEEG together with hepatic function and coagulation tests may be useful for the differential diagnosis of AE.

Imaging of extrapontine myelinolysis preceding central pontine myelinolysis in a case of ornithine transcarbamylase deficiency with hyperammonaemia and hypokalaemia.

Background: Patients with ornithine transcarbamylase deficiency (OTCD) often present with severe hyperammonaemia. We report a case of osmotic demyelination syndrome (ODS) secondary to the treatment of hyperammonaemia due to OTCD, a disease requiring early diagnosis, as it can have a severe prognosis. Case: A girl toddler was brought to the hospital with a complaint of somnolence, presenting with hyperammonaemia and liver failure, and was diagnosed with OTCD. Treatment was started immediately, and the ammonia level returned to the normal range within 24 hours. On days 13-20, another treatment was commenced for re-elevated ammonia levels, which subsequently returned to within the reference range; however, mildly impaired consciousness persisted. Hypokalaemia coincided with temporary intravenous treatment and continuous haemodialysis. T2-weighted magnetic resonance images revealed lesions as high-signal areas in the bilateral putamen on day 11 (extrapontine myelinolysis (EPM)) and in the pons on day 51 (central pontine myelinolysis (CPM)). Consequently, ODS was diagnosed. Conclusion: When interpreting magnetic resonance images of patients under acute treatment for hyperammonaemia due to OTCD, a condition that may be complicated by hypokalaemia, paying attention to findings suggesting EPM may help detect ODS before CPM appears and may improve patient prognosis.

Auditory Cortex Neurons Show Task-Related and Learning-Dependent Selectivity toward Sensory Input and Reward during the Learning Process of an Associative Memory Task.

The activity of primary auditory cortex (A1) neurons is modulated not only by sensory inputs but also by other task-related variables in associative learning. However, it is unclear how A1 neural activity changes dynamically in response to these variables during the learning process of associative memory tasks. Therefore, we developed an associative memory task using auditory stimuli in rats. In this task, rats were required to associate tone frequencies (high and low) with a choice of ports (right or left) to obtain a reward. The activity of A1 neurons in the rats during the learning process of the task was recorded. A1 neurons increased their firing rates either when the rats were presented with a high or low tone (frequency-selective cells) before they chose either the left or right port (choice-direction cells), or when they received a reward after choosing either the left or right port (reward-direction cells). Furthermore, the proportion of frequency-selective cells and reward-direction cells increased with task acquisition and reached the maximum level in the last stage of learning. These results suggest that A1 neurons have task- and learning-dependent selectivity toward sensory input and reward when auditory tones and behavioral responses are gradually associated during task training. This selective activity of A1 neurons may facilitate the formation of associations, leading to the consolidation of associative memory.

Medial prefrontal cortex stimulation disrupts observational learning in Barnes maze in rats.

Observational learning, which improves one's own behavior by observing the adaptive behavior of others, has been experimentally demonstrated in primates and rodents in several behavioral studies, including our previous study. However, its neural mechanisms remain unclear. We electrically stimulated the brain regions of rats and disturbed their neural activities during observation periods in the observational learning task using Barnes maze. According to comparison of escaping latencies of the observer and model rats, the observer rats with stimulation of the medial prefrontal cortex (mPFC) showed no observational learning, whereas both of the observer rats with stimulation of the dorsal hippocampus and with no stimulation (control) showed observational learning. These results suggest that mPFC stimulation disrupts observational learning and confirms that the mPFC is an important brain region for it in rats.

Hippocampal CA1 Neurons Represent Positive Feedback During the Learning Process of an Associative Memory Task.

The hippocampus is crucial for forming associations between environmental stimuli. However, it is unclear how neural activities of hippocampal neurons dynamically change during the learning process. To address this question, we developed an associative memory task for rats with auditory stimuli. In this task, the rats were required to associate tone pitches (high and low) and ports (right and left) to obtain a reward. We recorded the firing activity of neurons in rats hippocampal CA1 during the learning process of the task. As a result, many hippocampal CA1 neurons increased their firing rates when the rats received a reward after choosing either the left or right port. We referred to these cells as "reward-direction cells." Furthermore, the proportion of the reward-direction cells increased in the middle-stage of learning but decreased after the completion of learning. This result suggests that the activity of reward-direction cells might serve as "positive feedback" signal that facilitates the formation of associations between tone pitches and port choice.

Over-representation of fundamental decision variables in the prefrontal cortex underlies decision bias.

The brain is organized into anatomically distinct structures consisting of a variety of projection neurons. While such evolutionarily conserved neural circuit organization underlies the innate ability of animals to swiftly adapt to environments, they can cause biased cognition and behavior. Although recent studies have begun to address the causal importance of projection-neuron types as distinct computational units, it remains unclear how projection types are functionally organized in encoding variables during cognitive tasks. This review focuses on the neural computation of decision making in the prefrontal cortex and discusses what decision variables are encoded by single neurons, neuronal populations, and projection type, alongside how specific projection types constrain decision making. We focus particularly on "over-representations" of distinct decision variables in the prefrontal cortex that reflect the biological and subjective significance of the variables for the decision makers. We suggest that task-specific over-representation in the prefrontal cortex involves the refinement of the given decision making, while generalized over-representation of fundamental decision variables is associated with suboptimal decision biases, including pathological ones such as those in patients with psychiatric disorders. Such over-representation of the fundamental decision variables in the prefrontal cortex appear to be tightly constrained by afferent and efferent connections that can be optogenetically intervened on. These ideas may provide critical insights into potential therapeutic targets for psychiatric disorders, including addiction and depression.

Bi-directional encoding of context-based odors and behavioral states by the nucleus of the lateral olfactory tract.

The nucleus of the lateral olfactory tract (NLOT) is not only a part of the olfactory cortex that receives olfactory sensory inputs but also a part of the cortical amygdala, which regulates motivational behaviors. To examine how neural activity of the NLOT is modulated by decision-making processes that occur during various states of learned goal-directed behaviors, we recorded NLOT spike activities of mice performing odor-guided go/no-go tasks to obtain a water reward. We observed that several NLOT neurons exhibited sharp go-cue excitation and persistent no-go-cue suppression responses triggered by an odor onset. The bidirectional cue encoding introduced NLOT population response dynamics and provided a high odor decoding accuracy before executing cue-odor-evoked behaviors. The go-cue responsive neurons were also activated in the reward drinking state, indicating context-based odor-outcome associations. These findings suggest that NLOT neurons play an important role in the translation from context-based odor information to appropriate behavior.

Contribution of non-sensory neurons in visual cortical areas to visually guided decisions in the rat.

It is widely assumed that trial-by-trial variability in visual detection performance is explained by the fidelity of visual responses in visual cortical areas influenced by fluctuations of internal states, such as vigilance and behavioral history. However, it is not clear which neuronal ensembles represent such different internal states. Here, we utilized a visual detection task, which distinguishes internal states in response to identical stimuli, while recording neurons simultaneously from the primary visual cortex (V1) and the posterior parietal cortex (PPC). We found that rats sometimes withheld their responses to visual stimuli despite the robust presence of visual responses in V1. Our unsupervised analysis revealed distinct population dynamics segregating hit responses from misses, orthogonally embedded to visual response dynamics in both V1 and PPC. Heterogeneous non-sensory neurons in V1 and PPC significantly contributed to population-level encoding accompanied with the modulation of noise correlation only in V1. These results highlight the non-trivial contributions of non-sensory neurons in V1 and PPC for population-level computations that reflect the animals' internal states to drive behavioral responses to visual stimuli.

Basilar Artery Dissection Complicated with Infective Endocarditis.

A 14 year-old boy developed infective endocarditis of the mitral valve caused by Methicillin-sensitive Staphylococcus aureus and became comatose. Isolated basilar artery dissection was initially observed on the 3rd day by magnetic resonance imaging (MRI), ie, it did not exist on day 1. He underwent successful urgent mitral valve repair on the 5th day because of highly mobile vegetations and a newly emerged brain infarction under optimal antibiotic administration. Postoperatively, he recovered well and the basilar artery dissection was found to have recovered on an MRI on the 25th day without any specific intervention. This clinical course indicated that intracranial artery dissection may occur as a complication of infective endocarditis and supports the importance of the careful evaluation of brain MRI in patients with infective endocarditis.

Markedly long pause due to sinus arrest during dexmedetomidine use and nasal continuous positive airway pressure in two infants with respiratory syncytial virus infection.

Nasal respiratory support for infants with respiratory distress caused by respiratory syncytial (RS) virus infection sometimes requires appropriate sedation. Dexmedetomidine can be an alternative sedative because of its advantage of less frequent respiratory suppression. We report the cases of twin infants with RS virus infection who showed unreported long pauses (4 and 10 s) due to sinus arrest while receiving dexmedetomidine. After termination of dexmedetomidine administration, the long pause of >2 s was no longer observed in both cases. RS virus infection may inhibit the conduction system and sometimes induce bradyarrhythmia. Cardiac and sinus arrests are reported as complications of dexmedetomidine administration. Thus, because dexmedetomidine administration and RS virus infection may additively or synergistically inhibit the conduction system, the use of dexmedetomidine in infantile RS infection should be carefully considered. If sedation is unavoidable, other drugs should be used first. An evidence-based safe regimen for sedation in infants with RS infection should be established in the near future. .

Dynamic coordination of the perirhinal cortical neurons supports coherent representations between task epochs.

Cortical neurons show distinct firing patterns across multiple task epochs characterized by different computations. Recent studies suggest that such distinct patterns underlie dynamic population code achieving computational flexibility, whereas neurons in some cortical areas often show coherent firing patterns across epochs. To understand how coherent single-neuron code contributes to dynamic population code, we analyzed neural responses in the rat perirhinal cortex (PRC) during cue and reward epochs of a two-alternative forced-choice task. We found that the PRC neurons often encoded the opposite choice directions between those epochs. By using principal component analysis as a population-level analysis, we identified neural subspaces associated with each epoch, which reflected coordination across the neurons. The cue and reward epochs shared neural dimensions where the choice directions were consistently discriminated. Interestingly, those dimensions were supported by dynamically changing contributions of the individual neurons. These results demonstrated heterogeneity of coherent single-neuron representations in their contributions to population code.

Tuning of olfactory cortex ventral tenia tecta neurons to distinct task elements of goal-directed behavior.

The ventral tenia tecta (vTT) is a component of the olfactory cortex and receives both bottom-up odor signals and top-down signals. However, the roles of the vTT in odor-coding and integration of inputs are poorly understood. Here, we investigated the involvement of the vTT in these processes by recording the activity from individual vTT neurons during the performance of learned odor-guided reward-directed tasks in mice. We report that individual vTT cells are highly tuned to a specific behavioral epoch of learned tasks, whereby the duration of increased firing correlated with the temporal length of the behavioral epoch. The peak time for increased firing among recorded vTT cells encompassed almost the entire temporal window of the tasks. Collectively, our results indicate that vTT cells are selectively activated during a specific behavioral context and that the function of the vTT changes dynamically in a context-dependent manner during goal-directed behaviors.

Contribution of the prefrontal cortex and basolateral amygdala to behavioral decision-making under reward/punishment conflict.

RATIONALE: Control of reward-seeking behavior under conditions of punishment is an important function for survival. OBJECTIVES AND METHODS: We designed a task in which rats could choose to either press a lever and obtain a food pellet accompanied by a footshock or refrain from pressing the lever to avoid footshock, in response to tone presentation. In the task, footshock intensity steadily increased, and the task was terminated when the lever press probability reached < 25% (last intensity). Rats were trained until the last intensity was stable. Subsequently, we investigated the effects of the pharmacological inactivation of the ventromedial prefrontal cortex (vmPFC), lateral orbitofrontal cortex (lOFC), and basolateral amygdala (BLA) on task performance. RESULTS: Bilateral inactivation of the vmPFC, lOFC, and BLA did not alter lever press responses at the early stage of the task. The number of lever presses increased following vmPFC and BLA inactivation but decreased following lOFC inactivation during the later stage of the task. The last intensity was elevated by vmPFC or BLA inactivation but lowered by lOFC inactivation. Disconnection of the vmPFC-BLA pathway induced behavioral alterations that were similar to vmPFC or BLA inactivation. Inactivation of any regions did not alter footshock sensitivity and anxiety levels. CONCLUSIONS: Our results demonstrate a strong role of the vmPFC and BLA and their interactions in reward restraint to avoid punishment and a prominent role of the lOFC in reward-seeking under reward/punishment conflict situations.

Left-right functional difference of the rat dorsal hippocampus for short-term memory and long-term memory.

The existence of left-right hemispheric differences has been suggested not only in humans but also in rodents. In recent studies, left-right anatomical and functional differences of the rodent hippocampus have been revealed. However, there is only one report investigating the left-right difference for short-term memory (STM), and the left-right difference for long-term memory (LTM) is not consistent among previous studies. Therefore, we examined the effects of unilateral hippocampal lesion and stimulation on the formation of STM and LTM in rats. Our results showed that the right, but not the left, hippocampal lesion impaired STM performance, evaluated by the alternation rate in the spontaneous alternation test and the novel-arm choice rate in the novelty preference test. In addition, electrical stimulation of the left, but not the right, hippocampus immediately before the tests impaired STM performance. On the other hand, the left, but not the right, hippocampal lesion impaired the LTM performance, evaluated by the discrimination index in the object recognition test. In addition, the stimulation of the left, but not the right, hippocampus impaired LTM performance. These results suggest that both the left and right hippocampi are involved in STM formation, and the right hippocampus has a facilitating role while the left hippocampus has a suppressing role for STM. On the other hand, LTM may be driven correctly only by the left hippocampus with appropriate level of neural activity. The left and right hippocampi of rodents may work in different mechanisms depending on the demand for STM and LTM.

Dynamics of memory engrams.

In this update article, we focus on "memory engrams", which are traces of long-term memory in the brain, and emphasizes that they are not static but dynamic. We first introduce the major findings in neuroscience and psychology reporting that memory engrams are sometimes diffuse and unstable, indicating that they are dynamically modified processes of consolidation and reconsolidation. Second, we introduce and discuss the concepts of cell assembly and engram cell, the former has been investigated by psychological experiments and behavioral electrophysiology and the latter is defined by recent combination of activity-dependent cell labelling with optogenetics to show causal relationships between cell population activity and behavioral changes. Third, we discuss the similarities and differences between the cell assembly and engram cell concepts to reveal the dynamics of memory engrams. We also discuss the advantages and problems of live-cell imaging, which has recently been developed to visualize multineuronal activities. The last section suggests the experimental strategy and background assumptions for future research of memory engrams. The former encourages recording of cell assemblies from different brain regions during memory consolidation-reconsolidation processes, while the latter emphasizes the multipotentiality of neurons and regions that contribute to dynamics of memory engrams in the working brain.

Reinforcement schedules differentially affect learning in neuronal operant conditioning in rats.

Operant conditioning of neuronal activity is a core process for better operation of brain-machine interfaces. However, few studies have investigated the role of reinforcement schedules in neuronal operant conditioning, although they are very effective in behavioral operant conditioning. To test the effect of different reinforcement schedules, the authors trained single-neuron activity in the motor cortex using fixed ratio (FR) and variable ratio (VR) schedules in rats. Neuronal firing rates were enhanced in the FR but not in the VR schedule during conditioning, suggesting that the principles of operant conditioning of neuronal activity are different from those of behavioral responses.