Efficient encoding of aversive location by CA3 long-range projections.

Memorizing locations that are harmful or dangerous is a key capability of all organisms and requires an integration of affective and spatial information. In mammals, the dorsal hippocampus mainly processes spatial information, while the intermediate to ventral hippocampal divisions receive affective information via the amygdala. However, how spatial and aversive information is integrated is currently unknown. To address this question, we recorded the activity of hippocampal long-range CA3 axons at single-axon resolution in mice forming an aversive spatial memory. We show that intermediate CA3 to dorsal CA3 (i-dCA3) projections rapidly overrepresent areas preceding the location of an aversive stimulus due to a spatially selective addition of new place-coding axons followed by spatially non-specific stabilization. This sequence significantly improves the encoding of location by the i-dCA3 axon population. These results suggest that i-dCA3 axons transmit a precise, denoised, and stable signal indicating imminent danger to the dorsal hippocampus.

Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy.

Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed a marked increase in the fraction of hippocampal first-order CA1 pyramidal cell dendrites capable of generating dendritic spikes in the kainate model of chronic epilepsy. Moreover, in epileptic mice dendritic spikes were generated with lower input synchrony, and with a lower threshold. The Nav1.3/1.1 selective Na+ channel blocker ICA-121431 reversed dendritic hyperexcitability in epileptic mice, while the Nav1.2/1.6 preferring anticonvulsant S-Lic did not. We used in vivo two-photon imaging to determine if aberrant dendritic excitability is associated with altered place-related firing of CA1 neurons. We show that ICA-121431 improves degraded hippocampal spatial representations in epileptic mice. Finally, behavioural experiments show that reversing aberrant dendritic excitability with ICA-121431 reverses hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.

Psychometric Properties of the Persian Version of Penn Parkinson Daily Activities Questionnaire-15.

Introduction: Appropriate information about the ability of patients with Parkinson disease (PD) to perform cognitive instrumental activities of daily living (IADL) is necessary. The present study aimed to assess the psychometric properties of the Persian version of the Penn Parkinson daily activities questionnaire-15 (PDAQ-15). Methods: A total of 165 knowledgeable informants of PD patients completed the PDAQ-15. The clinical dementia rating scale, Hoehn and Yahr staging, hospital anxiety and depression scale (HADS), and Lawton IADL scale were used in the study. Internal consistency and test-retest reliability were evaluated by the Cronbach α coefficient and intraclass correlation coefficient (ICC), respectively. To examine the dimensionality of the questionnaire, exploratory factor analysis was used. The construct validity was assessed using the Spearman rank correlation test. To assess the discriminative validity, PDAQ-15 scores were compared across cognitive stages. Results: The PDAQ-15 showed strong internal consistency (the Cronbach α=0.99) and test-retest reliability (ICC= 0.99). Only one dimension was identified for the PDAQ-15 in the factor analysis. There was a strong correlation between PDAQ-15 with the depression domain of the HADS scale and the Lawton IADL scale (rs=|0.71-0.95|). The correlation of PDAQ-15 with the anxiety domain of the HADS scale was moderate (rs=0.66). Discriminative validity analysis showed that the PDAQ-15 has significant power to discriminate between PD patients across cognitive stages. Conclusion: These results suggest that the PDAQ-15 is a valid and reliable PD-specific instrument and can be useful in clinical and research settings.

Synchronous activity patterns in the dentate gyrus during immobility.

The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in vivo two-photon Ca2+ imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they are more similar than expected by chance to population patterns evoked during self-motion. Using optogenetic inhibition, we show that granule cell activity is not only required during exploration, but also during immobility in order to form dentate gyrus-dependent spatial memories.

The Association of Balance, Fear of Falling, and Daily Activities With Drug Phases and Severity of Disease in Patients With Parkinson.

INTRODUCTION: In the elderly, functional balance, fear of falling, and independence in daily living activities are interrelated; however, this relationship may change under the influence of drug phase and the severity of disease in individuals with idiopathic Parkinson disease. This study aimed to investigate the association of functional balance, fear of falling, and independence in the Activities of Daily Living (ADL) with the drug on- and drug off-phases. METHODS: A total of 140 patients with Parkinson disease (age: Mean±SD; 60.51±12.32 y) were evaluated in terms of their functional balance, fear of falling, and independence in their daily activities by the Berg Balance Scale (BBS), Fall Efficacy Scale-International (FES-I), and Unified Parkinson Disease Rating Scale-ADL (UPDRS-ADL), respectively, in drug on- and drug off-phases. The Hoehn and Yahr scale recorded global disease rating. The Spearman coefficient, Kruskal-Wallis, and Mann-Whitney tests were used to find out whether the distribution of scale scores differs with regard to functional balance or disease severity. RESULTS: A strong correlation was found between the functional balance, fear of falling, and independence in ADL with both drug phases. The results also showed the significant difference in the distribution of the FES-I and UPDRS-ADL scores with regard to functional balance (except independence in ADL in drug off-phase). Also, the distribution of the scores of BBS, FES-I, and UPDRS-ADL showed significant differences with regard to disease severity. CONCLUSION: The study showed a strong correlation between functional balance, fear of falling, and independence in ADL that can be affected by the drug phase and severity of the disease. However, more studies are needed to understand this relationship precisely.

Psychometric properties of the Berg balance scale in idiopathic Parkinson' disease in the drug off-phase.

BACKGROUND: Having an appropriate tool for assessment of the balance status during the drug off-phase in idiopathic Parkinson's disease (PD) is relevant for clinical and research settings. Our objective was to assess the clinimetric properties of the Berg balance scale (BBS) during drug off-phase in PD. METHOD: Balance of 98 PD patients (mean age ± SD, 59.19 ± 10.88 years) was evaluated with the BBS. Other assessments in the study included the Fall Efficacy Scale-International (FES-I), Functional Reach Test (FRT), Section II of the Unified Parkinson's Disease Rating Scale-3.0, Parkinson's Disease Questionnaire-39 (PDQ-39), and Schwab and England Activities of Daily Living Scale. All evaluations took place during the drug off-phase. Internal consistency and inter- and intra-rater reliability were evaluated by Cronbach's alpha coefficient and intraclass correlation coefficient, respectively. Dimensionality was explored by factor analysis. Discriminative validity was tested by comparing BBS score between PD patients with and without a history of falling. RESULTS: Internal consistency was high (α = 0.98), as were intra- and inter-rater reliability (ICC = 0.98 and 0.95, respectively). Factor analysis identified only one dimension for the BBS, whose convergent validity with FES-I, FRT, and domain mobility of the PDQ-39 were moderate or high (rS = |0.60-0.74|). Correlation of BBS with functional scales and PDQ-39 Summary Index was moderate (rS = |0.45-0.62|). Finally, the BBS showed a moderate strength to discriminate between PD patients with and without a history of falling. CONCLUSION: Our study suggests that BBS has satisfactory internal consistency, reliability, and construct validity for measuring functional balance in people with PD during the drug off-phase.

Function and developmental origin of a mesocortical inhibitory circuit.

Midbrain ventral tegmental neurons project to the prefrontal cortex and modulate cognitive functions. Using viral tracing, optogenetics and electrophysiology, we found that mesocortical neurons in the mouse ventrotegmental area provide fast glutamatergic excitation of GABAergic interneurons in the prefrontal cortex and inhibit prefrontal cortical pyramidal neurons in a robust and reliable manner. These mesocortical neurons were derived from a subset of dopaminergic progenitors, which were dependent on prolonged Sonic Hedgehog signaling for their induction. Loss of these progenitors resulted in the loss of the mesocortical inhibitory circuit and an increase in perseverative behavior, whereas mesolimbic and mesostriatal dopaminergic projections, as well as impulsivity and attentional function, were largely spared. Thus, we identified a previously uncharacterized mesocortical circuit contributing to perseverative behaviors and found that the diversity of dopaminergic neurons begins to be established during their progenitor phase.