Modulation of corticothalamic circuits

Activation of the cortico-thalamic-cortical (CTC) network occurs normally in sleep but can also occur in pathological conditions such as absence epilepsy. There is also evidence that this network becomes less functional during aging and during neurodegenerative conditions such as Alzheimer's disease (AD).
Recent studies have shown that the neuromodulator adenosine, which acts at A1 receptors to reduce neuronal activity, plays a key role in controlling CTC network oscillations. Levels of adenosine in the brain vary with activity and build up to produce a drive to sleep. A1 receptors are expressed in the thalamus and reduce/abolish oscillations upon activation. Blocking A1 receptors enhances oscillations and thus endogenous adenosine binding to A1 receptors represents an endogenous feedback mechanism for oscillation control (10.1016/j.neuropharm.2022.109172).
One of the aims of this study is to use novel pharmacological compounds to dissect apart the effects of adenosine on the CTC network. BNOCPA is a novel A1 receptor agonist which shows remarkable selectivity between G proteins, only activating the Golb isoform ( 10.1038/s41467-022-31652-2). This unique property will enable study of the exact mechanisms by which adenosine regulates oscillations.
Tau is a protein that aggregates during sleep deprivation and in tauopathies such as AD. It is well established that these aggregates can modulate neuron function and neuronal communication. A further aim of this project is to determine if these tau aggregates modulate thalamic oscillations and through which specific mechanisms.
The major methodologies used in this study include extracellular recording of activity from ex vivo slices, whole cell patch clamp recording and detailed quantitative analysis.