Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1G86R and FusΔNLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1G93A and FusΔNLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

Gamma oscillatory complexity conveys behavioral information in hippocampal networks.

The hippocampus and entorhinal cortex exhibit rich oscillatory patterns critical for cognitive functions. In the hippocampal region CA1, specific gamma-frequency oscillations, timed at different phases of the ongoing theta rhythm, are hypothesized to facilitate the integration of information from varied sources and contribute to distinct cognitive processes. Here, we show that gamma elements -a multidimensional characterization of transient gamma oscillatory episodes- occur at any frequency or phase relative to the ongoing theta rhythm across all CA1 layers in male mice. Despite their low power and stochastic-like nature, individual gamma elements still carry behavior-related information and computational modeling suggests that they reflect neuronal firing. Our findings challenge the idea of rigid gamma sub-bands, showing that behavior shapes ensembles of irregular gamma elements that evolve with learning and depend on hippocampal layers. Widespread gamma diversity, beyond randomness, may thus reflect complexity, likely functional but invisible to classic average-based analyses.

How Many Gammas? Redefining Hippocampal Theta-Gamma Dynamic During Spatial Learning.

The hippocampal formation is one of the brain systems in which the functional roles of coordinated oscillations in information representation and communication are better studied. Within this circuit, neuronal oscillations are conceived as a mechanism to precisely coordinate upstream and downstream neuronal ensembles, underlying dynamic exchange of information. Within a global reference framework provided by theta (θ) oscillations, different gamma-frequency (γ) carriers would temporally segregate information originating from different sources, thereby allowing networks to disambiguate convergent inputs. Two γ sub-bands were thus defined according to their frequency (slow γ, 30-80 Hz; medium γ, 60-120 Hz) and differential power distribution across CA1 dendritic layers. According to this prevalent model, layer-specific γ oscillations in CA1 would reliably identify the temporal dynamics of afferent inputs and may therefore aid in identifying specific memory processes (encoding for medium γ vs. retrieval for slow γ). However, this influential view, derived from time-averages of either specific γ sub-bands or different projection methods, might not capture the complexity of CA1 θ-γ interactions. Recent studies investigating γ oscillations at the θ cycle timescale have revealed a more dynamic and diverse landscape of θ-γ motifs, with many θ cycles containing multiple γ bouts of various frequencies. To properly capture the hippocampal oscillatory complexity, we have argued in this review that we should consider the entirety of the data and its multidimensional complexity. This will call for a revision of the actual model and will require the use of new tools allowing the description of individual γ bouts in their full complexity.

Frequency matters: how changes in hippocampal theta frequency can influence temporal coding, anxiety-reduction, and memory.

Hippocampal theta frequency is a somewhat neglected topic relative to theta power, phase, coherence, and cross-frequency coupling. Accordingly, here we review and present new data on variation in hippocampal theta frequency, focusing on functional associations (temporal coding, anxiety reduction, learning, and memory). Taking the rodent hippocampal theta frequency to running-speed relationship as a model, we identify two doubly-dissociable frequency components: (a) the slope component of the theta frequency-to-stimulus-rate relationship ("theta slope"); and (b) its y-intercept frequency ("theta intercept"). We identify three tonic determinants of hippocampal theta frequency. (1) Hotter temperatures increase theta frequency, potentially consistent with time intervals being judged as shorter when hot. Initial evidence suggests this occurs via the "theta slope" component. (2) Anxiolytic drugs with widely-different post-synaptic and pre-synaptic primary targets share the effect of reducing the "theta intercept" component, supporting notions of a final common pathway in anxiety reduction involving the hippocampus. (3) Novelty reliably decreases, and familiarity increases, theta frequency, acting upon the "theta slope" component. The reliability of this latter finding, and the special status of novelty for learning, prompts us to propose a Novelty Elicits Slowing of Theta frequency (NEST) hypothesis, involving the following elements: (1) Theta frequency slowing in the hippocampal formation is a generalised response to novelty of different types and modalities; (2) Novelty-elicited theta slowing is a hippocampal-formation-wide adaptive response functioning to accommodate the additional need for learning entailed by novelty; (3) Lengthening the theta cycle enhances associativity; (4) Even part-cycle lengthening may boost associativity; and (5) Artificial theta stimulation aimed at enhancing learning should employ low-end theta frequencies.

A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies.

SCN1A (NaV1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms. It is not yet clear whether SCN1A mutations are necessary for the development of severe phenotypes or just for promoting seizures. A relevant example is the pleiotropic R1648H mutation that can cause either mild GEFS+ or severe DS. We used a R1648H knock-in mouse model (Scn1aRH/+) with mild/asymptomatic phenotype to dissociate the effects of seizures and of the mutation per se. The induction of short repeated seizures, at the age of disease onset for Scn1a mouse models (P21), had no effect in WT mice, but transformed the mild/asymptomatic phenotype of Scn1aRH/+ mice into a severe DS-like phenotype, including frequent spontaneous seizures and cognitive/behavioral deficits. In these mice, we found no major modifications in cytoarchitecture or neuronal death, but increased excitability of hippocampal granule cells, consistent with a pathological remodeling. Therefore, we demonstrate for our model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se, may increase the risk of second hits to develop severe phenotypes.

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 on the etiology of AD. 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 that 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 revisits these major results to show how this hypothesis provided the drive for the development of anticholinesterase inhibitor-based therapies of AD, the almost exclusively 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 on the basis of two sets of evidence from new animal models and refined imagery techniques in humans. First, human and animal studies agree in detecting signs of cholinergic dysfunctions much earlier than initially believed. Second, alterations of the cholinergic system are deeply intertwined with its reactive responses, providing the brain with efficient compensatory mechanisms to delay the conversion into AD. Active research in this field should provide new insight into development of multitherapies incorporating cholinergic manipulation, as well as early biomarkers of AD enabling 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.

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."

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.

Anticipatory reward signals in ventral striatal neurons of behaving rats.

It has been proposed that the striatum plays a crucial role in learning to select appropriate actions, optimizing rewards according to the principles of 'Actor-Critic' models of trial-and-error learning. The ventral striatum (VS), as Critic, would employ a temporal difference (TD) learning algorithm to predict rewards and drive dopaminergic neurons. This study examined this model's adequacy for VS responses to multiple rewards in rats. The respective arms of a plus-maze provided rewards of varying magnitudes; multiple rewards were provided at 1-s intervals while the rat stood still. Neurons discharged phasically prior to each reward, during both initial approach and immobile waiting, demonstrating that this signal is predictive and not simply motor-related. In different neurons, responses could be greater for early, middle or late droplets in the sequence. Strikingly, this activity often reappeared after the final reward, as if in anticipation of yet another. In contrast, previous TD learning models show decremental reward-prediction profiles during reward consumption due to a temporal-order signal introduced to reproduce accurate timing in dopaminergic reward-prediction error signals. To resolve this inconsistency in a biologically plausible manner, we adapted the TD learning model such that input information is nonhomogeneously distributed among different neurons. By suppressing reward temporal-order signals and varying richness of spatial and visual input information, the model reproduced the experimental data. This validates the feasibility of a TD-learning architecture where different groups of neurons participate in solving the task based on varied input information.