A second wind for the cholinergic system in Alzheimer’s therapy:

Notwithstanding tremendous research efforts, the cause of Alzheimer’s disease (AD) remains elusive and there is no curative treatment. The cholinergic hypothesis presented 35 years ago was the first major evidence-based hypothesis regarding AD etiology. It proposed that the depletion of brain acetylcholine was a primary cause of cognitive decline in advanced age and AD. It relied on a series of observations obtained in aged animals, elderly and AD patients which pointed to dysfunctions of cholinergic basal forebrain, similarities between cognitive impairments induced by anticholinergic drugs and those found in advanced age and AD, and beneficial effects of drugs stimulating cholinergic activity. This review comes back on these major results to show how this hypothesis provided the drive for the development of anticholinesterase inhibitor-based therapies of AD, the almost exclusive approved treatment in use despite transient and modest efficacy. New ideas for improving cholinergic therapies are also compared and discussed in light of the current revival of the cholinergic hypothesis based on two sets of evidence from new animal models and refined imagery techniques in humans. First, human and animal studies agree on detecting signs of cholinergic dysfunctions much earlier than initially thought. Second, alterations of the cholinergic system are deeply intertwined with its reactive responses providing the brain with efficient compensatory mechanisms to delay the conversion to AD. Active research in this field should give new insight to develop multi-therapies incorporating cholinergic manipulation, as well as early biomarkers of AD allowing earlier diagnostics. This is of prime importance to counteract a disease that is now recognized to start early in adult life

Novelty and anxiolytic drugs dissociate two components of hippocampal theta in behaving rats

Hippocampal processing is strongly implicated in both spatial cognition and anxiety and is temporally organized by the theta rhythm. However, there has been little attempt to understand how each type of processing relates to the other in behaving animals, despite their common substrate. In freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds used during foraging. A recent model predicts that spatial-translation-related and arousal/anxiety-related mechanisms of hippocampal theta generation underlie dissociable aspects of the theta frequency–running speed relationship (the slope and intercept, respectively). Here we provide the first confirmatory evidence: environmental novelty decreases slope, whereas anxiolytic drugs reduce intercept. Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior. Variation in intercept predicted anxiety-like behavior. Our findings isolate and doubly dissociate two components of theta generation that operate in parallel in behaving animals and link them to anxiolytic drug action, novelty, and the metric for self-motion

A specific role for septohippocampal acetylcholine in memory?

Acetylcholine has long been implicated in memory, including hippocampal-dependent memory, but the specific role for this neurotransmitter is difficult to identify in human neuropsychology. Here, we review the evidence for a mechanistic model of acetylcholine function within the hippocampus and consider its explanatory power for interpreting effects resulting from both pharmacological anticholinergic manipulations and lesions of the cholinergic input to the hippocampus in animals. We argue that these effects indicate that acetylcholine is necessary for some, but not all, hippocampal-dependent processes. We review recent evidence from lesion, pharmacological and electrophysiological studies to support the view that a primary function of septohippocampal acetylcholine is to reduce interference in the learning process by adaptively timing and separating encoding and retrieval processes. We reinterpret cholinergic-lesion based deficits according to this view and propose that acetylcholine reduces the interference elicited by the movement of salient locations between events

Evidence for encoding versus retrieval scheduling in the hippocampus by theta phase and acetylcholine

The formation of new memories requires new information to be encoded in the face of proactive interference from the past. Two solutions have been proposed for hippocampal region CA1: (1) acetylcholine, released in novelty, selectively suppresses excitatory projections to CA1 from CA3 (mediating the products of retrieval), while sparing entorhinal inputs (mediating novel sensory information) and (2) encoding preferentially occurs at the pyramidal-layer theta peak, coincident with input from entorhinal cortex, and retrieval occurs at the trough, coincident with input from CA3, consistent with theta phase-dependent synaptic plasticity. We examined three predictions of these models: (1) in novel environments, the preferred theta phase of CA1 place cell firing should shift closer to the CA1 pyramidal-layer theta peak, shifting the encoding-retrieval balance toward encoding; (2) the encoding-related shift in novel environments should be disrupted by cholinergic antagonism; and (3) in familiar environments, cholinergic antagonism should shift the preferred theta firing phase closer to the theta trough, shifting the encoding-retrieval balance even further toward retrieval. We tested these predictions by recording from CA1 pyramidal cells in freely moving rats as they foraged in open field environments under the influence of scopolamine (an amnestic cholinergic antagonist) or vehicle (saline). Results confirmed all three predictions, supporting both the theta phase and cholinergic models of encoding versus retrieval dynamics. Also consistent with cholinergic enhancement of encoding, scopolamine attenuated the formation of distinct spatial representations in a new environment, reducing the extent of place cell “remapping.

Theta phase precession of grid and place cell firing in open environments

Place and grid cells in the rodent hippocampal formation tend to fire spikes at successively earlier phases relative to the local field potential theta rhythm as the animal runs through the cell's firing field on a linear track. However, this ‘phase precession’ effect is less well characterized during foraging in two-dimensional open field environments. Here, we mapped runs through the firing fields onto a unit circle to pool data from multiple runs. We asked which of seven behavioural and physiological variables show the best circular–linear correlation with the theta phase of spikes from place cells in hippocampal area CA1 and from grid cells from superficial layers of medial entorhinal cortex. The best correlate was the distance to the firing field peak projected onto the animal's current running direction. This was significantly stronger than other correlates, such as instantaneous firing rate and time-in-field, but similar in strength to correlates with other measures of distance travelled through the firing field. Phase precession was stronger in place cells than grid cells overall, and robust phase precession was seen in traversals through firing field peripheries (although somewhat less than in traversals through the centre), consistent with phase coding of displacement along the current direction. This type of phase coding, of place field distance ahead of or behind the animal, may be useful for allowing calculation of goal directions during navigation