Dopamine facilitates associative memory encoding in the entorhinal cortex.

Mounting evidence shows that dopamine in the striatum is critically involved in reward-based reinforcement learning1,2. However, it remains unclear how dopamine reward signals influence the entorhinal-hippocampal circuit, another brain network that is crucial for learning and memory3-5. Here, using cell-type-specific electrophysiological recording6, we show that dopamine signals from the ventral tegmental area and substantia nigra control the encoding of cue-reward association rules in layer 2a fan cells of the lateral entorhinal cortex (LEC). When mice learned novel olfactory cue-reward associations using a pre-learned association rule, spike representations of LEC fan cells grouped newly learned rewarded cues with a pre-learned rewarded cue, but separated them from a pre-learned unrewarded cue. Optogenetic inhibition of fan cells impaired the learning of new associations while sparing the retrieval of pre-learned memory. Using fibre photometry, we found that dopamine sends novelty-induced reward expectation signals to the LEC. Inhibition of LEC dopamine signals disrupted the associative encoding of fan cells and impaired learning performance. These results suggest that LEC fan cells represent a cognitive map of abstract task rules, and that LEC dopamine facilitates the incorporation of new memories into this map.

Similarity in Neuronal Firing Regimes across Mammalian Species.

UNLABELLED: The architectonic subdivisions of the brain are believed to be functional modules, each processing parts of global functions. Previously, we showed that neurons in different regions operate in different firing regimes in monkeys. It is possible that firing regimes reflect differences in underlying information processing, and consequently the firing regimes in homologous regions across animal species might be similar. We analyzed neuronal spike trains recorded from behaving mice, rats, cats, and monkeys. The firing regularity differed systematically, with differences across regions in one species being greater than the differences in similar areas across species. Neuronal firing was consistently most regular in motor areas, nearly random in visual and prefrontal/medial prefrontal cortical areas, and bursting in the hippocampus in all animals examined. This suggests that firing regularity (or irregularity) plays a key role in neural computation in each functional subdivision, depending on the types of information being carried. SIGNIFICANCE STATEMENT: By analyzing neuronal spike trains recorded from mice, rats, cats, and monkeys, we found that different brain regions have intrinsically different firing regimes that are more similar in homologous areas across species than across areas in one species. Because different regions in the brain are specialized for different functions, the present finding suggests that the different activity regimes of neurons are important for supporting different functions, so that appropriate neuronal codes can be used for different modalities.

[Association between smoking and tuberculosis infection].

PURPOSE: Several reports show smoking as a risk factor of tuberculosis (TB) infection, especially in prisoners, emigrants, the homeless, or people in areas where TB is endemic. These reports mostly used the tuberculin test to detect TB. However, there is no report evaluating smoking as a risk factor of TB infection among people coming into contact with TB with the use of the Interferon-Gamma Release Assays (IGRA) test. MATERIAL & METHOD: We compared TB infection in smokers and non-smokers who came into contact with TB infection by using the IGRA test. We retrospectively collected information about people coming into contact with TB who visited the Daiichi Dispensary from July 1, 2011 to June 30, 2012. They were divided into 2 groups (IGRA positive or negative) and smoking (present/past or never). RESULT: Out of 390 subjects who came into contact with TB examined, 229 were male and 161 were female. The mean age was 39.0 years, 98 were present smokers, 69 were past smokers, and 223 were never-smokers. There were 19 IGRA-positive and 371 IGRA-negative subjects. The IGRA positive rate was 4.9%. Out of 19 IGRA-positive subjects, 13 were smokers or ever-smoker (68.4%). Out of 371 IGRA-negative subjects, 154 cases were smoker or ever-smoker (41.5%). Smoking experience (present and past) was statistically significant in the IGRA-positive group. There were no significant differences in sex, age, drinking habits, and level of contact. Multivariate analysis showed smoking was only one independent risk factor for being IGRA-positive (odds ratio 3.06, 95% confidence interval: 1.14-8.21, p = 0.027). DISCUSSION: Our results suggest that smoking experience in subjects coming into contact with TB is a risk factor for TB infection. TB cases in smokers are reported to be more severe and have delayed detection of disease. They are also more likely to infect those who come in contact with them. If TB source cases and their contacts are both smokers and co-exist in a narrow and limited area, the contacts might be at higher risk of exposure to TB-contaminated air than non-smokers.

[Liver dysfunction during treatment of latent tuberculosis infection].

PURPOSE: The indications for treatment for latent tuberculosis infection were revised in 2007 to reflect that any subject with a higher risk of tuberculosis regardless of age should be treated. We worried about the incidence of liver dysfunction due to isoniazid (INH) in patients older than 30 yrs. of age. We evaluated the frequency of liver dysfunction due to INH according to age and discussed the possibility of its prevention. METHODS: We reviewed the clinical records of 99 patients younger than 29 yrs. and 229 patients older than 30 yrs. who were treated for latent tuberculosis infection from August 2007 to December 2008 at our clinic. The liver function tests (AST and ALT) were performed before the treatment, one and a half months after the start of the treatment, and almost every month during the treatment. We defined liver dysfunction as an AST and/or ALT greater than 100 IU/L. RESULTS: Seven out of the 99 younger patients (7.1%) and 42 out of the 229 (18.3%) older patients developed liver dysfunction. The difference between the two age groups was statistically significant according to the chi-square test (p < 0.01). After the occurrence of liver dysfunction, 35 out of 49 patients (71%) completed the treatment by maintaining the same or a decreased dose of INH, while the medication was discontinued in 9 patients who were then followed up by chest X-ray examination. Two of these 49 patients discontinued the medication by themselves. CONCLUSIONS: The frequency of liver damage due to INH was higher in persons older than 30 yrs. In this group, 3 persons developed severe liver damage with ALT and/or AST higher than 1000 IU/L. Early detection is required to avoid serious damage. Thus, we decided to perform liver function tests more often, i.e., at 2 weeks after the onset of treatment and every month thereafter.

Enhanced Theta and High-Gamma Coupling during Late Stage of Rule Switching Task in Rat Hippocampus.

Hippocampal oscillations, particularly theta (6-12 Hz) and gamma (30-90 Hz) frequency bands, play an important role in several cognitive functions. Theta and gamma oscillations show cross-frequency coupling (CFC), wherein the phase of theta rhythm modulates the amplitude of the gamma oscillation, and this CFC is believed to reflect cell assembly dynamics in cognitive processes. Previous studies have reported that CFC strength correlates with the learning process. However, details on these dynamic correlations have not been elucidated. In the present study, we analyzed local field potentials recorded from the rat hippocampus during the learning of a rule-switching task. The modulation index, an index of the CFC strength, became higher in rule-guided behavior than in the no rule condition. The enhanced coupling between theta and high-gamma oscillations (60-90 Hz) changed during the late stage of learning. In contrast, the coupling between theta and low-gamma oscillations (30-60 Hz) did not show any changes during learning. These results suggest that the coupling between theta and gamma bands occurs during rule learning and that high- and low-gamma bands play different roles in rule switching.

Gamma oscillations in the entorhinal-hippocampal circuit underlying memory and dementia.

Gamma oscillations that occur within the entorhinal cortex-hippocampal circuitry play important roles in the formation and retrieval of memory in healthy brains. Recent studies report that gamma oscillations are impaired in the entorhinal-hippocampal circuit of Alzheimer's disease (AD) patients and AD animal models. Here we review the latest advancements in studies of entorhinal-hippocampal gamma oscillations in healthy memory and dementia. This review is especially salient for readers in Alzheimer's research field not familiar with in vivo electrophysiology. Recent studies have begun to show a causal link between gamma oscillations and AD pathology, suggesting that gamma oscillations may even offer a plausible future therapeutic target.

[Adverse effect other than liver dysfunction in treatment of latent tuberculous infection by isoniazid].

PURPOSE: To study the frequency and degree of adverse effect, other than liver dysfunction, of isoniazid (INH) preventive therapy in Japanese people. OBJECT AND METHOD: Chart review of Japanese persons who started isoniazid preventive chemotherapy in the two clinics in Tokyo, from 2003/1/1 to 2004/12/31. RESULT: There were 779 cases who did not transiently or completely stop INH preventive therapy because of adverse effect, and 20 cases who stopped INH transiently or completely because of adverse effect other than liver damage (total 799 cases). Of those cases, 153 cases (153/799=19.1%) experienced one or more adverse effect other than liver damage, and 20 cases (20/799=2.5%) of these 153 cases stopped INH transiently (12 cases) or completely (8 cases). For each category of adverse effect, digestive system symptoms were most frequent (5.9%), and then in frequency order, lethargy or easy-fatigability (4.6%), central nervous symptoms (4.5%), skin eruptions (2.6%), acne (2.5%), alcohol intolerance-like symptoms (2.5%), peripheral neuropathy (0.4%), arthralgia or limb pain (0.3%). Adverse effect requiring stopping INH transiently or completely were skin eruption (1.3%), digestive system symptoms (1.1%), central nervous symptoms (0.6%), acne (0.1%). Most of the adverse effect were not serious, and not required hospitalization. In isoniazid (INH) preventive therapy in Japanese people, adverse effect other than liver damage were not infrequent, but most of them are not serious, and do not disturb continuation of preventive therapy in most cases.

Impaired In Vivo Gamma Oscillations in the Medial Entorhinal Cortex of Knock-in Alzheimer Model.

The entorhinal cortex (EC) has bidirectional connections with the hippocampus and plays a critical role in memory formation and retrieval. EC is one of the most vulnerable regions in the brain in early stages of Alzheimer's disease (AD), a neurodegenerative disease with progressive memory impairments. Accumulating evidence from healthy behaving animals indicates gamma oscillations (30-100 Hz) as critical for mediating interactions in the circuit between EC and hippocampus. However, it is still unclear whether gamma oscillations have causal relationship with memory impairment in AD. Here we provide the first evidence that in vivo gamma oscillations in the EC are impaired in an AD mouse model. Cross-frequency coupling of gamma (30-100 Hz) oscillations to theta oscillations was reduced in the medial EC of anesthetized amyloid precursor protein knock-in (APP-KI) mice. Phase locking of spiking activity of layer II/III pyramidal cells to the gamma oscillations was significantly impaired. These data indicate that the neural circuit activities organized by gamma oscillations were disrupted in the medial EC of AD mouse model, and point to gamma oscillations as one of possible mechanisms for cognitive dysfunction in AD patients.

[Liver damage in treatment of latent tuberculous infection by isoniazid].

PURPOSE: To study the frequency and degree of liver damage as adverse effect of isoniazid (INH) preventive therapy in Japanese people. OBJECT AND METHOD: Chart review of Japanese persons who started isoniazid preventive chemotherapy in the two clinics in Tokyo, from 2003/1/1 to 2004/12/31. RESULT: There were 779 cases who did not transiently or completely stop INH preventive therapy because of adverse effect, and 26 cases who stopped INH transiently or completely because of liver damage as adverse effect (total 805 cases). In 371 cases, of those 779 cases, AST (asparate aminotransferase) and ALT (alanine aminotransferase) was measured after starting INH at least once. In 14.9% (59/397) of these 391 cases (= 371 + 26), liver damage as adverse effect was found. In 1.51% (6/397), liver damage with AST and/or ALT higher than 400 IU/L was found. Clinical hepatitis, associated with clinical symptom of hepatitis, was seen in 0.37% (3/805). Hepatitis with liver failure was seen in 0.12%. There was no death due to liver damage. CONCLUSION: Liver damage as adverse effect of isoniazid (INH) preventive therapy in Japanese people is not rare.

Theta oscillation and neuronal activity in rat hippocampus are involved in temporal discrimination of time in seconds.

The discovery of time cells revealed that the rodent hippocampus has information regarding time. Previous studies have suggested that the role of hippocampal time cells is to integrate temporally segregated events into a sequence using working memory with time perception. However, it is unclear whether hippocampal cells contribute to time perception itself because most previous studies employed delayed matching-to-sample tasks that did not separately evaluate time perception from working memory processes. Here, we investigated the function of the rat hippocampus in time perception using a temporal discrimination task. In the task, rats had to discriminate between durations of 1 and 3 s to get a reward, and maintaining task-related information as working memory was not required. We found that some hippocampal neurons showed firing rate modulation similar to that of time cells. Moreover, theta oscillation of local field potentials (LFPs) showed a transient enhancement of power during time discrimination periods. However, there were little relationships between the neuronal activities and theta oscillations. These results suggest that both the individual neuronal activities and theta oscillations of LFPs in the hippocampus have a possibility to be engaged in seconds order time perception; however, they participate in different ways.

[Preventive therapy in middle-aged and elderly persons selected from the population-based screening by mass miniature radiography--methodological aspect and adverse reactions].

The notification rate of tuberculosis in Japan was 31.0 per 100,000 in 2000. The rate was especially high among the elderly population, reaching 85.5 per 100,000 among those over 65 years of age. We conducted a study of preventive therapy in middle-aged and elderly persons selected from the population-based screening by the mass miniature radiography. The eligible criteria were 50-79 years of age, fibrous lesion which were compatible with healed tuberculosis and showed no change for at least one year, no previous treatment for tuberculosis, normal liver function tests, and no serious disease at the time of study. The eligible criteria for liver function tests in this study was less than 50 IU/L of AST and ALT value, and less than 1.5 mg/dl of T-bil level. A total of 13,219 people underwent TB screening in 4 cities in 1997 and 2 cities in 1998. Among them, 440 persons fulfilled the above criteria based on the screening records and chest X-ray films. The municipal offices sent letters to 418 people, except 22 whose addresses were unknown, to obtain permission to use their addresses and results of screening in our study. Permission was obtained from 137 persons and we sent them invitation letters for cost-free physical checkup service. Ninety-five persons visited us, and we offered them physical checkup and explained about our study. After obtaining the informed consent, we performed chest X-ray and sputum examination for 3 consecutive days. Finally 29 people were enrolled in the study. They were divided into 4 groups by sex and age, and were randomly assigned to one of two treatment groups. One group took 300 mg of INH per day for 6 months and the other group was only followed up by chest X-ray. Fourteen out of 29 persons began to take INH and received monthly liver function test. All the subjects were scheduled to follow by medical checkup every 6 months for 5 years. The proportion of taking INH tablets was estimated to range from 94% to 100%, based on the calendar for record of taking medication and the number of remaining tablets each month. Six (42.9%) of 14 persons reported adverse reactions. Two of 6 persons complained some of diarrhea, vomiting and gastrointestinal disturbance within 2 weeks, and discontinued taking INH, although none of them showed abnormal liver function tests. Two of 6 persons who reported some kinds of symptoms and 2 of 8 persons who did not complain of any symptoms showed abnormal liver function tests. The abnormal liver function tests had developed from 2 months after the beginning of INH taking in most of the persons and the abnormality improved after the completion of 6-month treatment. We have followed them for a maximum duration of 2.5 years, and 3 cases dropped out from the study. These defaulted cases had completed 6 months of INH. One person (69 y.o. male) was diagnosed as active TB by his chest X-ray film at the 6th month medical checkup, although it was not confirmed bacteriologically. One person (62 y.o. female) had the mastectomy for breast cancer 7 months before the entry to this study and relapsed at the 8th month after the entry. One person (73 y.o. female) was diagnosed as lung cancer at the medical checkup on 2.5 years. Besides them, 4 persons were suspected of worsening the abnormal shadows on chest X-ray films; one was from the INH group and three were from the follow-up group. However none of them was diagnosed clinically and bacteriologically as active tuberculosis.

Diverse synchrony of firing reflects diverse cell-assembly coding in the prefrontal cortex.

In the present paper, we focus on the coding by cell assemblies in the prefrontal cortex (PFC) and discuss the diversity of the coding, which results in stable and dynamic representations and the processing of various information in that higher brain region. The key activity that reflects cell-assembly coding is the synchrony of the firing of multiple neurons when animals are performing cognitive and memory tasks. First, we introduce some studies that have shown task-related synchrony of neuronal firing in the monkey PFC. These studies have reported fixed and several types of dynamic synchronous firing during working memory, long-term visual memory, and goal selection. The results of these studies have indicated that cell assemblies in the PFC can contribute to both the stability and the dynamics of various types of information. Second, we refer to rat studies and introduce the findings of cellular interactions that contribute to synchrony in working memory, learning-induced changes in synchrony in spatial tasks, and interactions of the PFC and hippocampus in dynamic synchrony. These studies have proposed neuronal mechanisms of cell-assembly coding in the PFC and its critical role in the learning of task demands in problematic situations. Based on the monkey and rat studies, we conclude that cell-assembly coding in the PFC is diverse and has various facets, which allow multipotentiality in the higher brain region. Finally, we discuss the problem of the sizes of cell assembly, how diverse the sizes are in the PFC, and the technical problems in their investigation. We introduce a unique spike-sorting method that can detect small and local cell assemblies that consist of closely neighboring neurons. Then, we describe the findings of our study that showed that the monkey PFC has both small and large cell assemblies, which have different roles in information coding in the working brain.