Gracianne E. Kmiec

The anterior cingulate cortex (ACC) plays a pivotal role in processing pain and emotion, communicating with both cortical and subcortical regions involved in these functions. The claustrum (CLA), a subcortical region with extensive connectivity to the ACC also plays a critical role in pain perception and consciousness. Both ACC and CLA express Kappa (KOR), Mu (MOR), and Delta (DOR) opioid receptors, yet whether and how opioid receptors modulate this circuit is poorly understood. This study investigates the effects of opioid receptor activation on glutamatergic signaling in CLA-ACC circuitry using spatial transcriptomics, slice electrophysiology, optogenetics, and pharmacological approaches in mice. Our results demonstrated that excitatory inputs generated by the CLA onto layer 5 pyramidal cells (L5 PYR) in the ACC are reduced by KOR, MOR, and DOR agonists. However, only KOR agonists reduce monosynaptic transmission from the CLA onto L5 ACC PYR cells, highlighting the unique role of KOR in modulating the CLA-ACC pathway. MOR agonists had a heterogeneous effect on optically-evoked excitatory postsynaptic currents (oEPSCs), significantly reducing longer-latency excitatory responses while only modestly inhibiting the short latency excitatory postsynaptic currents. DOR agonists only reduce slower, longer-latency recurrent excitatory responses. These findings provide new insights into how opioid receptors regulate the claustro-cingulate circuit and demonstrate the distinct, receptor-specific modulation of synaptic transmission within this network.

Tau pathology in the locus coeruleus (LC) is associated with several neurodegenerative conditions including Alzheimer’s disease and frontotemporal dementia. Phosphorylated tau accumulates in the LC and results in inflammation, synaptic loss, and eventually cell death as the disease progresses. Loss of LC neurons and noradrenergic innervation is thought to contribute to the symptoms of cognitive decline later in disease. While loss and degeneration of LC neurons has been well studied, less is known about changes in LC physiology at advanced stages of tau pathology that precedes neurodegeneration. In this study, we investigated the ex vivo electrophysiological properties of LC neurons in male and female mice from the P301S mouse model of tauopathy at 9 months of age, a time-point when significant tau accumulation, cell death, and cognitive impairments are observed. We found a reduction in excitatory inputs and changes in excitatory post-synaptic current kinetics in male and female P301S. There was also a decrease in spontaneous discharge of LC neurons and an increase in AP threshold in P301S mice of both sexes. Finally, we observed a decrease in excitability and increase in rheobase current in P301S mice. Despite the decrease in LC activity in slice, we did not identify differences in total tissue norepinephrine (NE) or NE metabolites in prefrontal cortex or hippocampus. Together these findings demonstrate reductions in the activity and excitability of LC neurons at late stages of tau accumulation. However, compensatory mechanisms may maintain normal NE levels in LC projection regions in vivo.