ARE THERE DISCRETE GAMMA SUB-BANDS IN HIPPOCAMPAL NETWORKS DURING SPATIAL LEARNING ?

International audienc

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

ARE THERE DISCRETE GAMMA SUB-BANDS IN HIPPOCAMPAL NETWORKS DURING SPATIAL LEARNING ?

International audienc

ARE THERE DISCRETE GAMMA SUB-BANDS IN HIPPOCAMPAL NETWORKS DURING SPATIAL LEARNING ?

International audienc

ARE THERE DISCRETE GAMMA SUB-BANDS IN HIPPOCAMPAL NETWORKS DURING SPATIAL LEARNING ?

International audienc

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

International audienceThe 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

Gamma oscillatory complexity conveys behavioral information in hippocampal networks

Abstract 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

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

International audienceSCN1A (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

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

International audienceAmyotrophic 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 Sod1 G86R and Fus Δ NLS/+ 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 SOD1 G93A and Fus Δ NLS/+ 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