Anthony T. Lee's research while affiliated with University of California, San Francisco and other places

Publications (10)

Behavioral tasks involving auditory cues activate inhibitory neurons within auditory cortex, leading to a reduction in the amplitude of auditory evoked response potentials (ERPs). One hypothesis is that this process, termed “task engagement,” may enable contextdependent behaviors. Here we set out to determine (1) whether the medial prefrontal cortex (mPFC) plays a role in task engagement and (2) how task engagement relates to the context-dependent processing of auditory cues in male and female mice performing a decisionmaking task that can be guided by either auditory or visual cues. We found that, in addition to auditory ERP suppression, task engagement is associated with increased mPFC activity and an increase in theta band (4–7 Hz) synchronization between the mPFC and auditory cortex. Optogenetically inhibiting the mPFC eliminates the task engagement-induced auditory ERP suppression, while also preventing mice from switching between auditory and visual cue-based rules. However, mPFC inhibition, which eliminates task engagementinduced auditory ERP suppression, did not prevent mice from making decisions based on auditory cues. Furthermore, a more specific manipulation, selective disruption of mPFC outputs to the mediodorsal (MD) thalamus, is sufficient to prevent switching between auditory and visual rules but does not affect auditory ERPs. Based on these findings, we conclude that (1) the mPFC contributes to both task engagement and behavioral flexibility; (2) mPFC-MD projections are important for behavioral flexibility but not task engagement; and (3) task engagement, evidenced by the suppression of cortical responses to sensory input, is not required for sensory cue-guided decision making.
Dopamine neurons in the ventral tegmental area (VTA) encode reward prediction errors and can drive reinforcement learning through their projections to striatum, but much less is known about their projections to prefrontal cortex (PFC). Here, we studied these projections and observed phasic VTA–PFC fiber photometry signals after the delivery of rewards. Next, we studied how optogenetic stimulation of these projections affects behavior using conditioned place preference and a task in which mice learn associations between cues and food rewards and then use those associations to make choices. Neither phasic nor tonic stimulation of dopaminergic VTA–PFC projections elicited place preference. Furthermore, substituting phasic VTA–PFC stimulation for food rewards was not sufficient to reinforce new cue–reward associations nor maintain previously learned ones. However, the same patterns of stimulation that failed to reinforce place preference or cue–reward associations were able to modify behavior in other ways. First, continuous tonic stimulation maintained previously learned cue–reward associations even after they ceased being valid. Second, delivering phasic stimulation either continuously or after choices not previously associated with reward induced mice to make choices that deviated from previously learned associations. In summary, despite the fact that dopaminergic VTA–PFC projections exhibit phasic increases in activity that are time locked to the delivery of rewards, phasic activation of these projections does not necessarily reinforce specific actions. Rather, dopaminergic VTA–PFC activity can control whether mice maintain or deviate from previously learned cue–reward associations.
Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST(+) interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST) interneurons, ectopic PV(+) projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG) power. Using medial ganglionic eminence (MGE) transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ∼30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6(+/-) mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-frequencies restored cognitive flexibility in adult Dlx5/6(+/-) mice. These pro-cognitive effects were frequency specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven γ oscillations in cognitive domains at the core of schizophrenia. VIDEO ABSTRACT: Copyright © 2015 Elsevier Inc. All rights reserved.
GABAergic projections from the neocortex to subcortical structures have been poorly characterized. Using Dlxi12b-Cre mice, we found anatomical evidence for GABAergic neurons that project from the mouse medial prefrontal cortex (mPFC) to multiple subcortical targets. We used a combination of patch-clamp electrophysiology, optogenetics, and pharmacology to confirm that Dlxi12b-labeled projections from the mPFC to the nucleus accumbens (NAcc) release GABA and do not corelease glutamate. Furthermore, optogenetic stimulation of these GABAergic projections from mPFC to NAcc induces avoidance behavior in a real-time place preference task, suggesting that these long-range projecting GABAergic neurons can transmit aversive signals. Finally, we found evidence for heterogeneous histochemical and/or electrophysiological properties of long-range projecting GABAergic neurons in the mPFC. Some of these neurons were labeled in parvalbumin-Cre and vasoactive intestinal peptide-Cre mice. We also used a novel intersectional targeting strategy to label GABAergic neurons in the mPFC that project to NAcc and found that these neurons have fast-spiking properties and express parvalbumin. These results define possible functions and properties for a class of long-range projecting GABAergic neurons in the neocortex.
Layer 5 pyramidal neurons comprise at least two subtypes: thick-tufted, subcortically projecting type A neurons, with prominent h-current, and thin-tufted, callosally projecting type B neurons, which lack prominent h-current. Using optogenetic stimulation, we find that these subtypes receive distinct forms of input that could subserve divergent functions. Repeatedly stimulating callosal inputs evokes progressively smaller excitatory responses in type B but not type A neurons. Callosal inputs also elicit more spikes in type A neurons. Surprisingly, these effects arise via distinct mechanisms. Differences in the dynamics of excitatory responses seem to reflect differences in presynaptic input, whereas differences in spiking depend on postsynaptic mechanisms. We also find that fast-spiking parvalbumin interneurons, but not somatostatin interneurons, preferentially inhibit type A neurons, leading to greater feedforward inhibition in this subtype. These differences may enable type A neurons to detect salient inputs that are focused in space and time, while type B neurons integrate across these dimensions.
Temporal lobectomy can lead to favorable seizure outcomes in medically-refractory temporal lobe epilepsy (TLE). While most studies focus on seizure-freedom after temporal lobectomy, less is known about seizure semiology in patients who "fail" surgery. Morbidity differs between seizure types that impair or spare consciousness. Among TLE patients with seizures after surgery, how does temporal lobectomy influence seizure type and frequency? To characterize seizure types and frequencies before and after temporal lobectomy for TLE, including consciousness-sparing or consciousness-impairing seizures. We performed a retrospective longitudinal cohort study examining patients undergoing temporal lobectomy for epilepsy at our institution from January 1995 to August 2010. Among 241 TLE patients who received temporal lobectomy, 174 (72.2%) patients achieved Engel class I outcome (free of disabling seizures), including 141 (58.5%) with complete seizure-freedom. Overall seizure frequency in patients with persistent postoperative seizures decreased by 70% (p < 0.01), with larger reductions in consciousness-impairing seizures. While the number of patients experiencing consciousness-sparing simple partial seizures (SPSs) decreased by only 19% after surgery, the number of individuals having consciousness-impairing complex partial seizures (CPSs) and generalized tonic-clonic seizures (GTCSs) diminished by 70% and 68%, respectively (p < 0.001). SPS was the predominant seizure type in 19.1% versus 37.0% of patients preoperatively and postoperatively, respectively (p < 0.001). Favorable seizure outcome was predicted by a lack of generalized seizures preoperatively (odds ratio 1.74, 95% confidence interval 1.06-2.86, p < 0.5). Given important clinical and mechanistic differences between seizures with or without impairment of consciousness, seizure type and frequency remain important considerations in epilepsy surgery.

Citations

Top co-authors (28)

Vikaas S. Sohal
  • University of California, San Francisco
Tosha Patel
  • University of California, San Francisco
Daniel L Vogt
  • Michigan State University
Kathleen K A Cho
  • University of California, San Francisco
Steven Gee
  • University of California, San Francisco
Dario J. Englot
  • Vanderbilt University
Renee V. Hoch
  • University of California, San Francisco
Catherine Tsai
  • University of California, San Francisco

Affiliations

University of California, San Francisco
Department
  • Department of Psychiatry

Publication Stats

Citations
336
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