The role of TASK-3 potassium channels in theta oscillations and behaviour

The two pore-domain potassium channel TASK-3 provides a potassium leak conductance in the mammalian brain and is activated by volatile anaesthetics. Previous studies have shown that TASK-3 knockout (KO) mice have a number of physiological and behavioural abnormalities. In particular, TASK-3 KO mice lack the type-2 theta oscillation (4-8 Hz) usually present in the electroencephalogram (EEG) under halothane anaesthesia, while the higher frequency type-1 theta oscillation (8-12 Hz) recorded during exploratory behaviour is unaffected. That TASK-3 KO mice also have moderate memory impairments, led us to ask whether there might be a link between type-2 theta deficits and impaired mnemonic behaviour. Our results indicate that TASK-3 KO mice also have impaired type-2 theta oscillations during freezing behaviour in a predator exposure test, suggesting possible sensorimotor integration problems. TASK-3 KO mice were found to have a mild impairment in working memory in the T-maze, but object recognition and emotional memory were intact, excluding a role for the TASK-3-dependent theta oscillation in these processes. Further studies then sought to understand the mechanistic role of TASK-3 in the theta oscillation using recombinant Adeno-associated viruses (rAAVs). We first investigated a possible functional role for the type-2 theta oscillation in mediating anaesthesia, and then confirmed that the halothane-associated theta oscillation was dependent upon cholinergic input from the medial septum to the hippocampus. TASK-3 was then re-expressed via rAAV in the medial septum in KO mice, resulting in partial rescue of the type-2 theta oscillation. Our results show that (1) the type-2 theta oscillation plays a redundant role in halothane anaesthesia, (2) type-2 theta deficits in TASK-3 KO mice have minimal effect on memory processing, and (3) that TASK-3 channels in the medial septum play a facilitatory role in type-2 theta oscillations

Spatial navigation and multiscale representation by hippocampal place cells

Hippocampal lesions are known to impair success in navigation tasks. While such tasks could be solved by memorizing complete paths from a starting location to the goal, animals still perform successfully when placed in a novel starting position. We propose a navigation algorithm to solve the latter problem by exploiting two facts about hippocampal organization: (1) The size of the place fields of hippocampal place cells varies systematically along the dorsoventral axis, with dorsal place cells having smaller place fields than ventral (Kjelstrup et. al. 2008); and (2) the theta oscillation propagates as a traveling wave from dorsal to ventral hippocampus (Lubenov and Siapas, 2009). Taken together, these observations imply that the hippocampal representation of space progresses from fine- to coarse-grained within every theta cycle. 

The algorithm assumes that place cells can be activated by the animal's imagining a goal location, in addition to physically standing in the appropriate location. In the proposed algorithm, place cell activation propagates from small scale to large scale until place cells are found which respond strongly to both the physical location and the goal location. These place fields have their centers aligned roughly in the direction of the goal, providing a crude estimate of which direction the animal should step to approach the goal. Fine-grained directional information is contained in the smaller scale place fields within these large ones. Our algorithm therefore identifies a sequence of place cells, one from each scale, whose centers lie roughly along the line to the goal. 

Simulations reveal successful navigation to the goal, even around obstacles. By minimizing the number of steps the animal takes to reach the goal, we predict the organization of the optimal place field "map"; specifically the fraction of place cells which should be allocated to each spatial scale. This prediction is, in principle, experimentally testable.

The set of place fields with centers lying along a line to the goal is used to compute a step direction by maximizing the probability that those cells will be active in the next time step, given that a particular step direction is chosen.

The proposed algorithm handles navigation around obstacles by including "border cells" (Solstad et. al. 2008) which inhibit place cells in proportion to the degree of overlap between the place field and the obstacle. Furthermore, including firing rate adaptation of place cells prevents the animal from getting stuck in one spot

A continuum model for the dynamics of the phase transition from slow-wave sleep to REM sleep

Previous studies have shown that activated cortical states (awake and rapid eye-movement (REM) sleep), are associated with increased cholinergic input into the cerebral cortex. However, the mechanisms that underlie the detailed dynamics of the cortical transition from slow-wave to REM sleep have not been quantitatively modeled. How does the sequence of abrupt changes in the cortical dynamics (as detected in the electrocorticogram) result from the more gradual change in subcortical cholinergic input? We compare the output from a continuum model of cortical neuronal dynamics with experimentally-derived rat electrocorticogram data. The output from the computer model was consistent with experimental observations. In slow-wave sleep, 0.5–2-Hz oscillations arise from the cortex jumping between “up” and “down” states on the stationary-state manifold. As cholinergic input increases, the upper state undergoes a bifurcation to an 8-Hz oscillation. The coexistence of both oscillations is similar to that found in the intermediate stage of sleep of the rat. Further cholinergic input moves the trajectory to a point where the lower part of the manifold in not available, and thus the slow oscillation abruptly ceases (REM sleep). The model provides a natural basis to explain neuromodulator-induced changes in cortical activity, and indicates that a cortical phase change, rather than a brainstem “flip-flop”, may describe the transition from slow-wave sleep to REM

Effects of the γ-secretase inhibitor semagacestat on hippocampal neuronal network oscillation

Neurological and psychiatric disorders are frequently associated with disruption of various cognitive functions, but development of effective drug treatments for these conditions has proven challenging. One of the main obstacles is the poor predictive validity of our preclinical animal models. In the present study the effects of the γ-secretase inhibitor semagacestat was evaluated in preclinical in vivo electrophysiological models. Recently disclosed Phase III findings on semagacestat indicated that Alzheimer’s disease (AD) patients on this drug showed significantly worsened cognitive function compared to those treated with placebo. Since previous studies have shown that drugs impairing cognitive function (including scopolamine, NMDA (N-methyl-D-aspartate) receptor antagonists, and nociceptin receptor agonists) disrupt or decrease power of elicited theta oscillation in the hippocampus, we tested the effects of acute and sub-chronic administration of semagacestat in this assay. Field potentials were recorded across the hippocampal formation with NeuroNexus multi-site silicon probes in urethane anesthetized male C57BL/6 mice; hippocampal CA1 theta oscillation was elicited by electrical stimulation of the brainstem nucleus pontis oralis. Sub-chronic administration of semagacestat twice daily over 12 days at a dose known to reduce beta-amyloid peptide (Aβ) level [100 mg/kg, p.o. (per oral)] diminished power of elicited hippocampal theta oscillation. Acute, subcutaneous administration of semagacestat (100 mg/kg) produced a similar effect on hippocampal activity. We propose that the disruptive effect of semagacestat on hippocampal function could be one of the contributing mechanisms to its worsening of cognition in patients with AD. As it has been expected, both acute and sub-chronic administrations of semagacestat significantly decreased Aβ40 and Aβ42 levels but the current findings do not reveal the mode of action of semagacestat in disrupting hippocampal oscillignificantly reduced braination

The Timing of Reward-Seeking Action Tracks Visually-Cued Theta Oscillations in Primary Visual Cortex

An emerging body of work challenges the view that primary visual cortex (V1) represents the visual world faithfully. Theta oscillations in the local field potential (LFP) of V1 have been found to convey temporal expectations and, specifically, to express the delay between a visual stimulus and the reward that it portends. We extend this work by showing how these oscillatory states in male, wild-type rats can even relate to the timing of a visually cued reward-seeking behavior. In particular, we show that, with training, high precision and accuracy in behavioral timing tracks the power of these oscillations and the time of action execution covaries with their duration. These LFP oscillations are also intimately related to spiking responses at the single-unit level, which themselves carry predictive timing information. Together, these observations extend our understanding of the role of cortical oscillations in timing generally and the role of V1 in the timing of visually cued behaviors specifically.Fil: Levy, Joshua M.. University Johns Hopkins; Estados UnidosFil: Zold, Camila Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Namboodiri, Vijay Mohan K.. University of North Carolina; Estados UnidosFil: Hussain Shuler, Marshall G. University Johns Hopkins; Estados Unido

Characterization of Continuously Oscillating Neurons (CONs) of the Medial Septum of Rats

Theta oscillation is the largest extracellular synchronous signal that can be recorded from the mammalian brain. It is known to influence information retention in the hippocampus, which plays a key role in declarative memory, recognition memory, working memory, and spatial memory. The theta oscillation field frequency is between 3 and 12 Hz and is present during exploratory behavior and sleep in rodents. Theta rhythm in the hippocampus is postulated to be produced by the rhythmical activity of pacemaking cells in the medial septumvertical limb of the diagonal band of Broca (MS-vDBB). Previous work in our laboratory demonstrated the existence of continuously oscillatory neurons (CONs), the pacemaking cells, and sporadically oscillatory neurons (SONs) in the MS-DB. CONs were found to fire rhythmical action potential bursts within the duration range of a theta wave. The frequency at which they fire correlates with the simultaneously recorded hippocampal theta rhythm. It is believed that inputs from CONs and other ascending neurons are necessary to recruit non-rhythmic neurons to fire along a theta oscillation pattern. Altogether, this initiates a propitious environment for hippocampal theta frequency, which becomes the foundation for memory formation important in neurodegenerative diseases such as Alzheimer’s disease (AD). The MS oscillatory mechanism is believed to lead and recruit theta rhythm generation in the hippocampus. However, the statedependent alterations of the septo-hippocampal connection and the possible imbalance leading to septal or hippocampal dominance are poorly understood. In our investigations, we report that our CON cell recording was immuno-reactive to vi a GABAergic marker, supporting our hypothesis that MS GABAergic neurons are key cells in pacing hippocampal theta. Additionally, we report our findings for one SON cell and one NON-NC cell recorded in the MS