PUBLICATIONS

We find the lateral parabrachial nuclei (LPBN) to the parafascicular (PF) thalamus circuitry drives coping responses in oxaliplatin-induced CIPN mice and is involved in both sensory and affective-motivational responses to cold allodynia, while the LPBN to the intralaminar centromedian (CM) thalamus circuitry is primarily involved in affective-motivational responses. 

Learning requires the coordinated activity of diverse cortical cell types, yet their individual contributions remain poorly understood. We show that CaMKII-dependent plasticity in distinct pyramidal tract neuron subtypes is essential for shaping premotor cortical dynamics that support motor timing learning, whereas plasticity in intratelencephalic neurons regulates cortical network organization without directly affecting behavioral performance. These findings reveal complementary cell-type-specific mechanisms that sculpt cortical dynamics during learning.

Hebbian synaptic plasticity is currently the main framework to relate neuronal activity, network structure, and learning and memory. However, recent experimental and computational modeling studies have revealed a new form of synaptic plasticity termed behavioral timescale synaptic plasticity (BTSP). It is triggered by dendritic plateau potentials associated with somatic burst firing, causes large changes in synaptic strength in a single shot, and operates on the timescale of seconds. Here we review the recent advances in our understanding of the circuit, cellular, and molecular mechanisms of BTSP, its prevalence in the brain, its role in shaping neuronal representations, and the emerging ideas regarding its contribution to different forms of learning. 

We investigated how dopaminergic signaling shapes cortical circuit dysfunction during chronic neuropathic pain. Combining electrophysiology, chemogenetics, gene-expression profiling, and circuit mapping, we found that dopamine D1 receptor signaling differentially regulates excitatory and inhibitory neurons in the anterior cingulate cortex. Neuropathic pain disrupts this balance, leading to cortical hyperexcitability, while restoring D1R signaling alleviates both pain hypersensitivity and anxiety-like behaviors. These findings identify mesocortical dopamine signaling as a key regulator of cortical plasticity and a potential therapeutic target for chronic pain. 

In this paper we investigated the molecular mechanisms underlying non-Hebbian behavioral time scale plasticity (BTSP) in hippocampal CA1 neurons, which underlies place cell formation. We show that BTSP can be induced in a single dendritic spine using two-photon glutamate uncaging paired with postsynaptic current injection temporally separated by a behavioral time scale. Using an improved Ca2+/calmodulin-dependent kinase II (CaMKII) sensor, we did not detect CaMKII activation during this BTSP induction. Instead, we observed dendritic, delayed and stochastic CaMKII activation (DDSC) associated with Ca2+ influx and plateau potentials 10–100 seconds after BTSP induction.

In this study we demonstrate cell type–specific roles of IGF1 and IGF2 in hippocampal plasticity as well as a plasticity mechanism mediated by the synthesis and autocrine signaling of IGF peptides in pyramidal neurons. Using a new fluorescence resonance energy transfer sensor for IGF1 receptor (IGF1R) with two-photon fluorescence lifetime imaging, we find that the release of IGF1 triggers rapid local autocrine IGF1R activation on the same spine and the stimulated dendrite, regulating the plasticity of the activated spine in CA1 pyramidal neurons. In CA3 neurons, IGF2, instead of IGF1, is responsible for IGF1R autocrine activation and synaptic plasticity. 

Excitatory synapses can be potentiated by 17β-estradiol (E2), or patterns of synaptic activation, as in long-term potentiation (LTP). In this paper, we investigated kinases and calcium sources required for acute E2-induced synaptic potentiation in the hippocampus. We found that, although E2 potentiates synapses to the same degree in each sex, cAMP-activated protein kinase (PKA) is required to initiate potentiation only in females. In contrast, Ca2+/calmodulin-activated kinase II is required for expression/maintenance of E2-induced potentiation in both sexes. To investigate the generalizability of this sex difference in the requirement for PKA in synaptic potentiation, we tested how PKA inhibition affects LTP. This showed that, although the magnitude of both high-frequency stimulation-induced and pairing-induced LTP is the same in both sexes, PKA is required for LTP in females but not males. 

As a followup of the previous paper, here we investigated whether the downstream consequences of distinct molecular signaling remain different between the sexes or converge to the same mechanism(s) for expression of potentiation. This study showed that synaptic activity is necessary for expression of E2-induced potentiation in females but not males, which paralleled a sex-specific requirement in females for calcium-permeable AMPARs (cpAMPARs) to stabilize potentiation. Lastly, in females, most synapses (76%) were potentiated via increased AMPAR conductance, whereas in males, more synapses (60%) were potentiated via an increase in nonconductive AMPAR properties.