Dataset Information

Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice.

ABSTRACT: Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). The absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why the absence of FMRP impairs memory discrimination and increases risk of autistic symptoms in patients, such as exaggerated responses to environmental changes. While Fmr1 knockout (KO) and wild-type (WT) mice perform cognitive discrimination tasks, we find abnormal patterns of coupling between theta and gamma oscillations in perisomatic and dendritic hippocampal CA1 local field potentials of the KO. Perisomatic CA1 theta-gamma phase-amplitude coupling (PAC) decreases with familiarity in both the WT and KO, but activating an invisible shock zone, subsequently changing its location, or turning it off, changes the pattern of oscillatory events in the LFPs recorded along the somato-dendritic axis of CA1. The cognition-dependent changes of this pattern of neural activity are relatively constrained in WT mice compared to KO mice, which exhibit abnormally weak changes during the cognitive challenge caused by changing the location of the shock zone and exaggerated patterns of change when the shock zone is turned off. Such pathophysiology might explain how dysregulated translation leads to intellectual disability in FXS. These findings demonstrate major functional abnormalities after the loss of FMRP in the dynamics of neural oscillations and that these impairments would be difficult to detect by steady-state measurements with the subject at rest or in steady conditions.

SUBMITTER: Radwan B

PROVIDER: S-EPMC4758895 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice.

Radwan Basma B Dvorak Dino D Fenton André A AA

Neurobiology of disease 20160112

Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). The absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why the absence of FMRP impairs memory discrimination and increases risk of autistic symptoms in patients, such as exaggerated responses to environmental changes. While Fmr1 ...[more]

PMID: 26792400

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Project description:Theta oscillations (4-8 Hz) provide an organizing principle of cognitive control, allowing goal-directed behavior. In adults, theta power over medial-frontal cortex (MFC) underlies conflict/error monitoring, whereas theta connectivity between MFC and lateral-frontal regions reflects cognitive control recruitment. However, prior work has not separated theta responses that occur before and immediately after a motor response, nor explained how medial-lateral connectivity drives different kinds of control behaviors. Theta's role during adolescence, a developmental window characterized by a motivation-control mismatch also remains unclear. As social observation is known to influence motivation, this might be a particularly important context for studying adolescent theta dynamics. Here, adolescents performed a flanker task alone or under social observation. Focusing first on the nonsocial context, we parsed cognitive control into dissociable subprocesses, illustrating how theta indexes distinct components of cognitive control working together dynamically to produce goal-directed behavior. We separated theta power immediately before/after motor responses, identifying behavioral links to conflict monitoring and error monitoring, respectively. MFC connectivity was separated before/after responses and behaviorally-linked to reactive and proactive control, respectively. Finally, distinct forms of post-error control were dissociated, based on connectivity with rostral/caudal frontal cortex. Social observation was found to exclusively upregulate theta measures indexing post-response error monitoring and proactive control, as opposed to conflict monitoring and reactive control. Linking adolescent cognitive control to theta oscillations provides a bridge between non-invasive recordings in humans and mechanistic studies of neural oscillations in animal models; links to social observation provide insight into the motivation-control interactions that occur during adolescence.

Project description:Theta-nested gamma oscillations have been reported in many areas of the brain and are believed to represent a fundamental mechanism to transfer information across spatial and temporal scales. In a series of recent experiments in vitro it has been possible to replicate with an optogenetic theta frequency stimulation several features of cross-frequency coupling (CFC) among theta and gamma rhythms observed in behaving animals. In order to reproduce the main findings of these experiments we have considered a new class of neural mass models able to reproduce exactly the macroscopic dynamics of spiking neural networks. In this framework, we have examined two set-ups able to support collective gamma oscillations: namely, the pyramidal interneuronal network gamma (PING) and the interneuronal network gamma (ING). In both set-ups we observe the emergence of theta-nested gamma oscillations by driving the system with a sinusoidal theta-forcing in proximity of a Hopf bifurcation. These mixed rhythms always display phase amplitude coupling. However, two different types of nested oscillations can be identified: one characterized by a perfect phase locking between theta and gamma rhythms, corresponding to an overall periodic behavior; another one where the locking is imperfect and the dynamics is quasi-periodic or even chaotic. From our analysis it emerges that the locked states are more frequent in the ING set-up. In agreement with the experiments, we find theta-nested gamma oscillations for forcing frequencies in the range [1:10] Hz, whose amplitudes grow proportionally to the forcing intensity and which are clearly modulated by the theta phase. Furthermore, analogously to the experiments, the gamma power and the frequency of the gamma-power peak increase with the forcing amplitude. At variance with experimental findings, the gamma-power peak does not shift to higher frequencies by increasing the theta frequency. This effect can be obtained, in our model, only by incrementing, at the same time, also the stimulation power. An effect achieved by increasing the amplitude either of the noise or of the forcing term proportionally to the theta frequency. On the basis of our analysis both the PING and the ING mechanism give rise to theta-nested gamma oscillations with almost identical features.

Dataset Information

Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice.

Publications

Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice.

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