Retrosplenial and Hippocampal Synchrony during Retrieval of Old Memories in Macaques.

Memory for events from the distant past relies on multiple brain regions, but little is known about the underlying neural dynamics that give rise to such abilities. We recorded neural activity in the hippocampus and retrosplenial cortex of two female rhesus macaques as they visually selected targets in year-old and newly acquired object-scene associations. Whereas hippocampal activity was unchanging with memory age, the retrosplenial cortex responded with greater magnitude alpha oscillations (10-15 Hz) and greater phase locking to memory-guided eye movements during retrieval of old events. A similar old-memory enhancement was observed in the anterior cingulate cortex but in a beta2/gamma band (28-35 Hz). In contrast, remote retrieval was associated with decreased gamma-band synchrony between the hippocampus and each neocortical area. The increasing retrosplenial alpha oscillation and decreasing hippocampocortical synchrony with memory age may signify a shift in frank memory allocation or, alternatively, changes in selection among distributed memory representations in the primate brain.SIGNIFICANCE STATEMENT Memory depends on multiple brain regions, whose involvement is thought to change with time. Here, we recorded neuronal population activity from the hippocampus and retrosplenial cortex as nonhuman primates searched for objects embedded in scenes. These memoranda were either newly presented or a year old. Remembering old material drove stronger oscillations in the retrosplenial cortex and led to a greater locking of neural activity to search movements. Remembering new material revealed stronger oscillatory synchrony between the hippocampus and retrosplenial cortex. These results suggest that with age, memories may come to rely more exclusively on neocortical oscillations for retrieval and search guidance and less on long-range coupling with the hippocampus.

Sharp-wave ripple features in macaques depend on behavioral state and cell-type specific firing.

Sharp-wave ripples (SWRs) are spontaneous, synchronized neural population events in the hippocampus widely thought to play a role in memory consolidation and retrieval. They occur predominantly in sleep and quiet immobility, and in primates, they also appear during active visual exploration. Typical measures of SWRs in behaving rats include changes in the rate of occurrence, or in the incidence of specific neural ensemble activity contained within the categorical SWR event. Much less is known about the relevance of spatiotemporal SWR features, though they may index underlying activity of specific cell types including ensemble-specific internally generated sequences. Furthermore, changes in SWR features during active exploratory states are unknown. In this study, we recorded hippocampal local-field potentials and single-units during periods of quiescence and as macaques performed a memory-guided visual search task. We observed that (a) ripples during quiescence have greater amplitudes and larger postripple waves (PRW) compared to those in task epochs, and (b) during "remembered" trials, ripples have larger amplitudes than during "forgotten" trials, with no change in duration or PRWs. We further found that spiking activity influences SWR features as a function of cell type and ripple timing. As expected, larger ripple amplitudes were associated with putative pyramidal or putative basket interneuron (IN) activity, even when the spikes in question exceed the duration of the ripple. In contrast, the PRW was attenuated with activity from low firing rate cells and enhanced with activity from high firing rate cells, with putative IN spikes during ripples leading to the most prominent PRW peaks. The selective changes in SWR features as a function of time window, cell type, and cognitive/vigilance states suggest that this mesoscopic field event can offer additional information about the local network and animal's state than would be appreciated from SWR event rates alone.

Theta- and gamma-band oscillatory uncoupling in the macaque hippocampus.

Nested hippocampal oscillations in the rodent give rise to temporal dynamics that may underlie learning, memory, and decision making. Although theta/gamma coupling in rodent CA1 occurs during exploration and sharp-wave ripples emerge in quiescence, it is less clear that these oscillatory regimes extend to primates. We therefore sought to identify correspondences in frequency bands, nesting, and behavioral coupling of oscillations taken from macaque hippocampus. We found that, in contrast to rodent oscillations, theta and gamma frequency bands in macaque CA1 were segregated by behavioral states. In both stationary and freely moving designs, beta2/gamma (15-70 Hz) had greater power during visual search whereas the theta band (3-10 Hz; peak ~8 Hz) dominated during quiescence and early sleep. Moreover, theta-band amplitude was strongest when beta2/slow gamma (20-35 Hz) amplitude was weakest, instead occurring along with higher frequencies (60-150 Hz). Spike-field coherence was most frequently seen in these three bands (3-10 Hz, 20-35 Hz, and 60-150 Hz); however, the theta-band coherence was largely due to spurious coupling during sharp-wave ripples. Accordingly, no intrinsic theta spiking rhythmicity was apparent. These results support a role for beta2/slow gamma modulation in CA1 during active exploration in the primate that is decoupled from theta oscillations. The apparent difference to the rodent oscillatory canon calls for a shift in focus of frequency when considering the primate hippocampus.

Locomotor activity, emotionality, sensori-motor gating, learning and memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease.

The APPswe/PS1dE9 mouse (line 85) is a double transgenic model of Alzheimer's disease (AD) with familial amyloid precursor protein and presenilin-1 mutations. These mice develop age-related behavioral changes reflective of the neuropsychiatric symptoms (altered anxiety-like behaviour, hyperactivity) and cognitive dysfunction (impaired learning and memory) observed in AD. The APPswe/PS1dE9 mouse has been used to examine the efficacy of therapeutic interventions on behaviour, despite previous difficulties in replicating behavioural phenotypes. Therefore, the purpose of this study was to establish the reliability of these phenotypes by further characterizing the behaviour of male APPswe/PS1dE9 and wild-type mice between 7 and 14 months of age. Mice were tested on the open-field over 5-days to examine emotionality, locomotor activity and inter-session habituation. Mice were also tested on the repeated-reversal water maze task and spontaneous alternation on the Y-maze to assess working memory. Sensori-motor gating was examined with acoustic startle and pre-pulse inhibition. Lastly contextual and cued (trace) memory was assessed with fear conditioning. The results show that among non-cognitive behaviours, APPswe/PS1dE9 mice have normal locomotor activity, anxiety-like behavior, habituation and sensori-motor gating. However, APPswe/PS1dE9 mice show impaired working memory on the repeated-reversal water-maze and impaired memory in contextual but not trace-cued fear conditioning. These results indicate that the APPswe/PS1dE9 (line 85) mice have deficits in some types of hippocampal-dependent learning and memory and, at the ages tested, APPswe/PS1dE9 mice model cognitive dysfunction but not neuropsychiatric symptoms.

Intracortical Microstimulation (ICMS) Activates Motor Cortex Layer 5 Pyramidal Neurons Mainly Transsynaptically.

BACKGROUND: Intracortical microstimulation (ICMS) is a technique used for a number of purposes including the derivation of cortical movement representations (motor maps). Its application can activate the output layer 5 of motor cortex and can result in the elicitation of body movements depending upon the stimulus parameters used. OBJECTIVE: The extent to which pyramidal tract projection neurons of the motor cortex are activated transsynaptically or directly by ICMS remains an open question. Given this uncertainty in the mode of activation, we used a preparation that combined patch clamp whole-cell recordings from single layer 5 pyramidal neurons and extracellular ICMS in slices of motor cortex as well as a standard in vivo mapping technique to ask how ICMS activated motor cortex pyramidal neurons. METHODS: We measured changes in synaptic spike threshold and spiking rate to ICMS in vitro and movement threshold in vivo in the presence or absence of specific pharmacological blockers of glutamatergic (AMPA, NMDA and Kainate) receptors and GABAA receptors. RESULTS: With major excitatory and inhibitory synaptic transmission blocked (with DNQX, APV and bicuculline methiodide), we observed a significant increase in the ICMS current intensity required to elicit a movement in vivo as well as to the first spike and an 85% reduction in spiking responses in vitro. Subsets of neurons were still responsive after the synaptic block, especially at higher current intensities, suggesting a modest direct activation. CONCLUSION: Taken together our data indicate a mainly synaptic mode of activation to ICMS in layer 5 of rat motor cortex.

Preparation and electrochromatographic characterization of new chiral ß-cyclodextrin poly(acrylamidopropyl) porous layer open tubular capillary columns.

A novel chiral stationary phase consisting of an amidopropyltrimethylammonium chloride divinylbenzene (APAT-DVB) polymer containing the chiral selector heptakis(2,3-di-O-acetyl-6-O-sulfo)-ß-cyclodextrin (HSßCD) has been employed in porous layer open tubular (PLOT) capillary column format with various conditions evaluated to optimize the polymerization and chiral selector immobilization. Scanning electron microscopy demonstrated a near homogenous longitudinal open path in the column with a polymer film of uniform thickness. IR spectroscopy characterized the functional groups of the polymer and energy-dispersive X-ray spectroscopy provided further evidence of the successful polymer modification with HSßCD. Optimum electrochromatographic separation conditions were elaborated with respect to organic solvent content and pH of the background electrolyte. Colum-to-column and long-term reproducibility was excellent. The effectiveness of the new capillary column was demonstrated with the successful separation of d-and l-aspartic acid, d- and l-tyrosine and d-and l-lysine.

The effect of chlordiazepoxide on measures of activity and anxiety in Swiss-Webster mice in the triple test.

The effects of the anxiolytic drug chlordiazepoxide (CDZ) on general activity and anxiety-related behaviour of male and female Swiss-Webster mice were investigated in the triple test, which combines the open field (OF), elevated-plus maze (EPM) and the light-dark box (LDB). Mice were injected with saline or CDZ (1.0, 7.5 or 15.0 mg/kg) and their behaviour was observed for 15 min in the triple test on each of two days. On day 1, increasing doses of CDZ increased open arm exploration and total distance travelled, and decreased risk assessments in the EPM. In the LDB, CDZ increased time in the light compartment and number of transitions between compartments. In spite of habituation to the apparatus, CDZ increased the number of transitions in the LDB, increased percent time in the open arms and total distance travelled in the EPM on day 2. Thus, there was a significant effect of CDZ in the triple test on both days, even though there was habituation to the apparatus after day 1. These results show that the drug effect was independent of the day effect and that there was no one-trial tolerance effect in the triple test of anxiety.

Measuring anxiety- and locomotion-related behaviours in mice: a new way of using old tests.

RATIONALE: Batteries of tests that are thought to measure different aspects of anxiety-related behaviour are used to characterise mice after genetic or pharmacological manipulation. However, because of the potentially confounding effects of repeated testing and natural intra-individual variations in behaviour over time, subjecting mice to a succession of tests is not ideal. OBJECTIVES: The aim of this study was to investigate, in mice, the utility of an integrated apparatus that combines three classical tests of anxiety, the open field, elevated plus maze (EPM) and light/dark box. METHODS: Mice from four different strains (CD-1, BALB/cJ, DBA/2J, C57BL/6J) were used in a series of five experiments where their behaviour was observed for 15 min in the integrated apparatus. Responses to anxiety-modulating drugs and 2-day repeated testing were evaluated. RESULTS: CD-1 mice explored the apparatus thoroughly, providing measures from all areas throughout the entire testing session. Factor analysis showed that measures of locomotion and anxiety-related behaviour were dissociable. BALB/cJ, DBA/2J and C57BL/6J showed markedly different behavioural profiles, largely consistent with previous studies examining individual tests. Avoidance of aversive environments did not increase with repeated testing. In CD-1 mice, the anxiolytics diazepam and alprazolam (4 and 2 mg/kg, respectively) increased the approach towards the EPM open arms. Alprazolam also had sedative effects, whereas the anxiogenic pentylenetetrazole had no effects. CONCLUSIONS: These findings suggest that the triple test is sensitive to genetic/pharmacological influences on anxiety and locomotion and that, by providing quasi-simultaneous measures from three different apparatuses, it may represent an alternative to the use of test batteries.