Transverse patterning,aging, and neuropsychological correlates in humans

Transverse patterning is a learning and memory adaptation of the ‘rock/paper/scissors’ problem that has been though to depend on the hippocampus, is sensitive to aging, and requires pattern separation to solve. Previous investigators dichotomized cognitively normal older adults who passed a cognitive screening into impaired and unimpaired subsets, and found that impaired older adults were disproportionately deficient in pattern separation abilities. However, this variability in pattern separation ability has not been examined using a transverse patterning task. Our aims, then, were two‐fold: First, to determine if impaired older adults were inferior on transverse patterning compared to unimpaired older adults and young adults; second, to identify the neuropsychological correlates of transverse patterning. Our findings revealed that impaired older adults required more trials to criterion on the transverse patterning task than both young adults and unimpaired older adults. Unimpaired older adults also required more trials to criterion than young adults. A detailed analysis of the transverse patterning task confirmed that the aforementioned group differences were only observed in high interference conditions when pattern separation demands were at their peak. Finally, regression analyses showed that both memory and executive functioning neuropsychological composite scores were related to different indices of transverse patterning performance. Consistent with the pattern separation literature, and despite passing a cognitive screening, we found disproportionate transverse patterning deficits in impaired older adults. Forthcoming work should determine if transverse patterning performance is similar between impaired older adults and patients with Mild Cognitive Impairment. © 2016 Wiley Periodicals, Inc.     

Dopaminergic system and dream recall: An MRI study in Parkinson's disease patients

We investigated the role of the dopamine system [i.e., subcortical‐medial prefrontal cortex (mPFC) network] in dreaming, by studying patients with Parkinson's Disease (PD) as a model of altered dopaminergic transmission. Subcortical volumes and cortical thickness were extracted by 3T‐MR images of 27 PD patients and 27 age‐matched controls, who were asked to fill out a dream diary upon morning awakening for one week. PD patients do not substantially differ from healthy controls with respect to the sleep, dream, and neuroanatomical measures. Multivariate correlational analyses in PD patients show that dopamine agonist dosage is associated to qualitatively impoverished dreams, as expressed by lower bizarreness and lower emotional load values. Visual vividness (VV) of their dream reports positively correlates with volumes of both the amygdalae and with thickness of the left mPFC. Emotional load also positively correlates with hippocampal volume. Beside the replication of our previous finding on the role of subcortical nuclei in dreaming experience of healthy subjects, this represents the first evidence of a specific role of the amygdala‐mPFC dopaminergic network system in dream recall. The association in PD patients between higher dopamine agonist dosages and impoverished dream reports, however, and the significant correlations between VV and mesolimbic regions, however, provide an empirical support to the hypothesis that a dopamine network plays a key role in dream generation. The causal relation is however precluded by the intrinsic limitation of assuming the dopamine agonist dosage as a measure of the hypodopaminergic state in PD. Hum Brain Mapp 37:1136–1147, 2016. © 2015 Wiley Periodicals, Inc .     

Spatial learning and neurogenesis: Effects of cessation of wheel running and survival of novel neurons by engagement in cognitive tasks

Physical exercise stimulates cell proliferation in the adult dentate gyrus and facilitates acquisition and/or retention of hippocampal‐dependent tasks. It is established that regular physical exercise improves cognitive performance. However, it is unclear for how long these benefits last after its interruption. Independent groups of rats received both free access to either unlocked (EXE Treatment) or locked (No‐EXE Treatment) running wheels for 7 days, and daily injections of bromodeoxyuridine (BrdU) in the last 3 days. After a time delay period of either 1, 3, or 6 weeks without training, the animals were tested in the Morris water maze (MWM) either in a working memory task dependent on hippocampal function (MWM‐HD) or in a visible platform searching task, independent on hippocampal function (MWM‐NH). Data confirmed that exposure of rats to 7 days of spontaneous wheel running increases cell proliferation and neurogenesis. In contrast, neurogenesis was not accompanied by significant improvements of performance in the working memory version of the MWM. Longer time delays between the end of exercise and the beginning of cognitive training in the MWM resulted in lower cell survival; that is, the number of novel surviving mature neurons was decreased when this delay was 6 weeks as compared with when it was 1 week. In addition, data showed that while exposure to the MWM‐HD working memory task substantially increased survival of novel neurons, exposure to the MWM‐NH task did not, thus indicating that survival of novel dentate gyrus neurons depends on the engagement of this brain region in performance of cognitive tasks. © 2015 Wiley Periodicals, Inc.     

Which way and how far? Tracking of translation and rotation information for human path integration

Path integration, the constant updating of the navigator's knowledge of position and orientation during movement, requires both visuospatial knowledge and memory. This study aimed to develop a systems‐level understanding of human path integration by examining the basic building blocks of path integration in humans. To achieve this goal, we used functional imaging to examine the neural mechanisms that support the tracking and memory of translational and rotational components of human path integration. Critically, and in contrast to previous studies, we examined movement in translation and rotation tasks with no defined end‐point or goal. Navigators accumulated translational and rotational information during virtual self‐motion. Activity in hippocampus, retrosplenial cortex (RSC), and parahippocampal cortex (PHC) increased during both translation and rotation encoding, suggesting that these regions track self‐motion information during path integration. These results address current questions regarding distance coding in the human brain. By implementing a modified delayed match to sample paradigm, we also examined the encoding and maintenance of path integration signals in working memory. Hippocampus, PHC, and RSC were recruited during successful encoding and maintenance of path integration information, with RSC selective for tasks that required processing heading rotation changes. These data indicate distinct working memory mechanisms for translation and rotation, which are essential for updating neural representations of current location. The results provide evidence that hippocampus, PHC, and RSC flexibly track task‐relevant translation and rotation signals for path integration and could form the hub of a more distributed network supporting spatial navigation. Hum Brain Mapp 37:3636–3655, 2016. © 2016 Wiley Periodicals, Inc .     

Characterization of a novel subtype of hippocampal interneurons that express corticotropin‐releasing hormone

A subset of corticotropin‐releasing hormone (CRH) neurons was previously identified in the hippocampus with unknown function. Here we demonstrate that hippocampal CRH neurons represent a novel subtype of interneurons in the hippocampus, exhibiting unique morphology, electrophysiological properties, molecular markers, and connectivity. This subset of hippocampal CRH neurons in the mouse reside in the CA1 pyramidal cell layer and tract tracing studies using AAV‐Flex‐ChR2‐tdTomato reveal dense back‐projections of these neurons onto principal neurons in the CA3 region of the hippocampus. These hippocampal CRH neurons express both GABA and GAD67 and using in vitro optogenetic techniques, we demonstrate that these neurons make functional connections and release GABA onto CA3 principal neurons. The location, morphology, and importantly the functional connectivity of these neurons demonstrate that hippocampal CRH neurons represent a unique subtype of hippocampal interneurons. The connectivity of these neurons has significant implications for hippocampal function. © 2015 Wiley Periodicals, Inc.     

17β estradiol recruits GluN2B‐containing NMDARs and ERK during induction of long‐term potentiation at temporoammonic‐CA1 synapses

When circulating 17β estradiol (E2) is elevated to proestrous levels, hippocampus‐dependent learning and memory is enhanced in female rodents, nonhuman primates, and women due to heightened synaptic function at hippocampal synapses. We previously reported that proestrous‐like levels of E2 administered to young adult ovariectomized (OVX) female rats increases the magnitude of LTP at CA3 Schaffer collateral (SC)‐CA1 synapses only when dendritic spine density, the NMDAR/AMPAR ratio, and current mediated by GluN2B‐containing NMDA receptors (NMDARs) are simultaneously increased. We also reported that this increase in GluN2B‐mediated NMDAR current in area CA1 is causally related to the E2‐induced increase in novel object recognition, tying together heightened synaptic function with improved learning and memory. In addition to SC inputs, innervation from the entorhinal cortex in the temporoammonic (TA) pathway onto CA1 distal dendrites in stratum lacunosum‐moleculare is critical for spatial memory formation and retrieval. It is not known whether E2 modulates TA‐CA1 synapses similarly to SC‐CA1 synapses. Here, we report that 24 hours post‐E2 injection, dendritic spine density on CA1 pyramidal cell distal dendrites and current mediated by GluN2B‐containing NMDARs at TA‐CA1 synapses is increased, similarly to our previous findings at SC‐CA1 synapses. However, in contrast to SC‐CA1 synapses, AMPAR transmission at TA‐CA1 synapses is significantly increased, and there is no effect on the LTP magnitude. Pharmacological blockade of GluN2B‐containing NMDARs or ERK activation, which occurs downstream of synaptic but not extrasynaptic GluN2B‐containing NMDARs, attenuates the LTP magnitude only in slices from E2‐treated rats. These data show that E2 recruits a causal role for GluN2B‐containing NMDARs and ERK signaling in the induction of LTP, cellular mechanisms not required for LTP induction at TA‐CA1 synapses in vehicle‐treated OVX female rats. © 2015 Wiley Periodicals, Inc.     

Cognitive state following mild stroke: A matter of hippocampal mean diffusivity

The hippocampus is known to play a vital role in learning and memory and was demonstrated as an early imaging marker for Alzheimer's disease (AD). However, its role as a predictor for mild cognitive impairment and dementia following stroke is unclear. The main purpose of this study was to examine the associations between hippocampal volume, mean diffusivity (MD) and connectivity and cognitive state following stroke. Eighty three consecutive first ever mild to moderate stroke or transient ischemic attack (TIA) survivors from our ongoing prospective TABASCO (Tel Aviv Brain Acute Stroke Cohort) study underwent magnetic resonance imaging scans within 7 days of stroke onset. Hippocampal volume was measured from T1 weighted images, hippocampal mean diffusivity was calculated from diffusion tensor imaging and connectivity was calculated from resting state fMRI. Global cognitive assessments were evaluated during hospitalization and 6 and 12 months later using a computerized neuropsychological battery. Multiple linear regression analysis was used to test which of the hippocampi measurements best predict cognitive state. All three imaging parameters were significantly correlated to each other (|r's| >0.3, P's < 0.005), and with cognitive state 6 and 12 months after the event. Multiple regression analyses demonstrated the predictive role of hippocampal mean diffusivity (β = ?0.382, P = 0.026) on cognitive state, above and beyond that of volume and connectivity of this structure. To our knowledge, the combination of hippocampal volume, mean diffusivity and connectivity in first ever post stroke or TIA patients has not yet been considered in relation to cognitive state. The results demonstrate the predictive role of hippocampal mean diffusivity, suggesting that these changes may precede and contribute to volumetric and connectivity changes in the hippocampi, potentially serving as a marker for early identification of patients at risk of developing cognitive impairment or dementia. © 2015 Wiley Periodicals, Inc.     

Mapping the electrophysiological and morphological properties of CA1 pyramidal neurons along the longitudinal hippocampal axis

Differences in behavioral roles, anatomical connectivity, and gene expression patterns in the dorsal, intermediate, and ventral regions of the hippocampus are well characterized. Relatively fewer studies have, however, focused on comparing the physiological properties of neurons located at different dorsoventral extents of the hippocampus. Recently, we reported that dorsal CA1 neurons are less excitable than ventral neurons. There is little or no information for how neurons in the intermediate hippocampus compare to those from the dorsal and ventral ends. Also, it is not known whether the transition of properties along the dorsoventral axis is gradual or segmented. In this study, we developed a statistical model to predict the dorsoventral position of transverse hippocampal slices. Using current clamp recordings combined with this model, we found that CA1 neurons in dorsal, intermediate, and ventral hippocampus have distinct electrophysiological and morphological properties and that the transition in most (but not all) of these properties from the ventral to dorsal end is gradual. Using linear and segmented regression analyses, we found that input resistance and resting membrane potential changed linearly along the V–D axis. Interestingly, the transition in resonance frequency, rebound slope, dendritic branching in stratum radiatum, and action potential properties was segmented along the V–D axis. Together, the findings from this study highlight the heterogeneity in CA1 neuronal properties along the entire longitudinal axis of hippocampus. © 2015 Wiley Periodicals, Inc.     

Increased Variability and Asymmetric Expansion of the Hippocampal Spatial Representation in a Distal Cue‐Dependent Memory Task

Place cells in the hippocampus fire at specific positions in space, and distal cues in the environment play critical roles in determining the spatial firing patterns of place cells. Many studies have shown that place fields are influenced by distal cues in foraging animals. However, it is largely unknown whether distal‐cue‐dependent changes in place fields appear in different ways in a memory task if distal cues bear direct significance to achieving goals. We investigated this possibility in this study. Rats were trained to choose different spatial positions in a radial arm in association with distal cue configurations formed by visual cue sets attached to movable curtains around the apparatus. The animals were initially trained to associate readily discernible distal cue configurations (0° vs. 80° angular separation between distal cue sets) with different food‐well positions and then later experienced ambiguous cue configurations (14° and 66°) intermixed with the original cue configurations. Rats showed no difficulty in transferring the associated memory formed for the original cue configurations when similar cue configurations were presented. Place field positions remained at the same locations across different cue configurations, whereas stability and coherence of spatial firing patterns were significantly disrupted when ambiguous cue configurations were introduced. Furthermore, the spatial representation was extended backward and skewed more negatively at the population level when processing ambiguous cue configurations, compared with when processing the original cue configurations only. This effect was more salient for large cue‐separation conditions than for small cue‐separation conditions. No significant rate remapping was observed across distal cue configurations. These findings suggest that place cells in the hippocampus dynamically change their detailed firing characteristics in response to a modified cue environment and that some of the firing properties previously reported in a foraging task might carry more functional weight than others when tested in a distal‐cue‐dependent memory task. © 2016 Wiley Periodicals, Inc.     

Cholinergic neuronal lesions in the medial septum and vertical limb of the diagonal bands of Broca induce contextual fear memory generalization and impair acquisition of fear extinction

Previous research has shown that the ventral medial prefrontal cortex (vmPFC) and hippocampus (Hipp) are critical for extinction memory. Basal forebrain (BF) cholinergic input to the vmPFC and Hipp is critical for neural function in these substrates, which suggests BF cholinergic neurons may be critical for extinction memory. In order to test this hypothesis, we applied cholinergic lesions to different regions of the BF and observed the effects these lesions had on extinction memory. Complete BF cholinergic lesions induced contextual fear memory generalization, and this generalized fear was resistant to extinction. Animals with complete BF cholinergic lesions could not acquire cued fear extinction. Restricted cholinergic lesions in the medial septum and vertical diagonal bands of Broca (MS/vDBB) mimicked the effects that BF cholinergic lesions had on contextual fear memory generalization and acquisition of fear extinction. Cholinergic lesions in the horizontal diagonal band of Broca and nucleus basalis (hDBB/NBM) induced a small deficit in extinction of generalized contextual fear memory with no accompanying deficits in cued fear extinction. The results of this study reveal that MS/vDBB cholinergic neurons are critical for inhibition and extinction of generalized contextual fear memory, and via this process, may be critical for acquisition of cued fear extinction. Further studies delineating neural circuits and mechanisms through which MS/vDBB cholinergic neurons facilitate these emotional memory processes are needed. © 2015 Wiley Periodicals, Inc.