Bachelor of Science, University of Science and Technology of China (2007)
Doctor of Philosophy, University of Southern California (2014)
Thomas Sudhof, Postdoctoral Faculty Sponsor
Dysfunction of parvalbumin neurons in the cerebellar nuclei produces an action tremor.
The Journal of clinical investigation
Essential tremor is a common brain disorder affecting millions of people, yet the neuronal mechanisms underlying this prevalent disease remain elusive. Here, we show that conditional deletion of synaptotagmin-2, the fastest Ca2+-sensor for synaptic neurotransmitter release, from parvalbumin neurons in mice causes an action tremor syndrome resembling the core symptom of essential tremor patients. Combining brain region-specific and cell type-specific genetic manipulation methods, we found that deletion of synaptotagmin-2 from excitatory parvalbumin-positive neurons in cerebellar nuclei was sufficient to generate an action tremor. The synaptotagmin-2 deletion converted synchronous into asynchronous neurotransmitter release in projections from cerebellar nuclei neurons onto gigantocellular reticular nucleus neurons, which might produce an action tremor by causing signal oscillations during movement. The tremor was rescued by completely blocking synaptic transmission with tetanus toxin in cerebellar nuclei, which also reversed the tremor phenotype in the traditional harmaline-induced essential tremor model. Using a promising animal model for action tremor, our results thus characterize a synaptic circuit mechanism that may underlie the prevalent essential tremor disorder.
View details for DOI 10.1172/JCI135802
View details for PubMedID 32634124
A central amygdala to zona incerta projection is required for acquisition and remote recall of conditioned fear memory.
The formation and retrieval of conditioned fear memories critically depend on the amygdala. Here we identify an inhibitory projection from somatostatin-positive neurons in the central amygdala to parvalbumin-positive neurons in the zona incerta that is required for both recent and remote fear memories. Thus, the amygdala inhibitory input to parvalbumin-positive neurons in the zona incerta, a nucleus not previously implicated in fear memory, is an essential component of the fear memory circuitry.
View details for PubMedID 30349111
Sparse Representation in Awake Auditory Cortex: Cell-type Dependence, Synaptic Mechanisms, Developmental Emergence, and Modulation.
Cerebral cortex (New York, N.Y. : 1991)
Sparse representation is considered an important coding strategy for cortical processing in various sensory modalities. It remains unclear how cortical sparseness arises and is being regulated. Here, unbiased recordings from primary auditory cortex of awake adult mice revealed salient sparseness in layer (L)2/3, with a majority of excitatory neurons exhibiting no increased spiking in response to each of sound types tested. Sparse representation was not observed in parvalbumin (PV) inhibitory neurons. The nonresponding neurons did receive auditory-evoked synaptic inputs, marked by weaker excitation and lower excitation/inhibition (E/I) ratios than responding cells. Sparse representation arises during development in an experience-dependent manner, accompanied by differential changes of excitatory input strength and a transition from unimodal to bimodal distribution of E/I ratios. Sparseness level could be reduced by suppressing PV or L1 inhibitory neurons. Thus, sparse representation may be dynamically regulated via modulating E/I balance, optimizing cortical representation of the external sensory world.
View details for DOI 10.1093/cercor/bhy260
View details for PubMedID 30307493
Scaling down of balanced excitation and inhibition by active behavioral states in auditory cortex
2014; 17 (6): 841-850
Cortical sensory processing is modulated by behavioral and cognitive states. How this modulation is achieved by changing synaptic circuits remains largely unknown. In awake mouse auditory cortex, we found that sensory-evoked spike responses of layer 2/3 (L2/3) excitatory cells were scaled down with preserved sensory tuning when mice transitioned from quiescence to active behaviors, including locomotion, whereas L4 and thalamic responses were unchanged. Whole-cell voltage-clamp recordings revealed that tone-evoked synaptic excitation and inhibition exhibited a robust functional balance. The change to active states caused scaling down of excitation and inhibition at approximately equal levels in L2/3 cells, but resulted in no synaptic changes in L4 cells. This lamina-specific gain control could be attributed to an enhancement of L1-mediated inhibitory tone, with L2/3 parvalbumin inhibitory neurons also being suppressed. Thus, L2/3 circuits can adjust the salience of output in accordance with momentary behavioral demands while maintaining the sensitivity and quality of sensory processing.
View details for DOI 10.1038/nn.3701
View details for Web of Science ID 000336638000020
View details for PubMedID 24747575
Synaptic Mechanisms for Generating Temporal Diversity of Auditory Representation in the Dorsal Cochlear Nucleus.
Journal of neurophysiology
In central auditory pathways neurons exhibit a great diversity of temporal discharge patterns, which may contribute to the parallel processing of auditory signals. How such response diversity emerges in the central auditory circuits remains unclear. Here, we investigated whether synaptic mechanisms can contribute to the generation of the temporal response diversity at the first stage along the central auditory neuraxis. By in vivo whole-cell voltage-clamp recording in the dorsal cochlear nucleus (DCN) of rats, we revealed excitatory and inhibitory synaptic inputs underlying three different firing patterns of fusiform/pyramidal neurons in response to auditory stimuli: "primary-like", "pauser", and "buildup" patterns. We found that primary-like neurons received strong fast-rising excitation, whereas pauser and buildup neurons received accumulating excitation with a relatively weak fast rising phase followed by a slow rising phase. Pauser neurons received stronger fast-rising excitation than buildup cells. On the other hand, inhibitory inputs to the three types of cell exhibited similar temporal patterns all with a strong fast-rising phase. Dynamic-clamp recordings demonstrated that the differential temporal patterns of excitation could primarily account for the different discharge patterns. In addition, discharge pattern in a single neuron varied in a stimulus-dependent manner, which could be attributed to the modulation of excitation/inhibition balance by different stimuli. Further examination of excitatory inputs to vertical/tuberculoventral and cartwheel cells suggested that fast-rising and accumulating excitation might be conveyed by auditory nerve and parallel fibers respectively. A differential summation of excitatory inputs from the two sources may thus contribute to the generation of response diversity.
View details for DOI 10.1152/jn.00573.2014
View details for PubMedID 25475349
Intracortical multiplication of thalamocortical signals in mouse auditory cortex
2013; 16 (9): 1179-U25
Cortical processing of sensory information begins with the transformation of thalamically relayed signals. We optogenetically silenced intracortical circuits to isolate thalamic inputs to layer 4 neurons and found that intracortical excitation linearly amplified thalamocortical responses underlying frequency and direction selectivity, with spectral range and tuning preserved, and prolonged the response duration. This signal pre-amplification and prolongation enhanced the salience of thalamocortically relayed information and ensured its robust, faithful and more persistent representation.
View details for DOI 10.1038/nn.3493
View details for Web of Science ID 000323597500006
View details for PubMedID 23933752
Generation of Intensity Selectivity by Differential Synaptic Tuning: Fast-Saturating Excitation But Slow-Saturating Inhibition
JOURNAL OF NEUROSCIENCE
2012; 32 (50): 18068-18078
Intensity defines one fundamental aspect of sensory information and is specifically represented in each sensory modality. Interestingly, only in the central auditory system are intensity-selective neurons evolved. These neurons are characterized by nonmonotonic response-level functions. The synaptic circuitry mechanisms underlying the generation of intensity selectivity from nonselective auditory nerve inputs remain largely unclear. Here, we performed in vivo whole-cell recordings from pyramidal neurons in the rat dorsal cochlear nucleus (DCN), where intensity selectivity first emerges along the auditory neuraxis. Our results revealed that intensity-selective cells received fast-saturating excitation but slow-saturating inhibition with intensity increments, whereas in intensity-nonselective cells excitation and inhibition were similarly slow-saturating. The differential intensity tuning profiles of the monotonic excitation and inhibition qualitatively determined the intensity selectivity of output responses. In addition, the selectivity was further strengthened by significantly lower excitation/inhibition ratios at high-intensity levels compared with intensity-nonselective neurons. Our results demonstrate that intensity selectivity in the DCN is generated by extracting the difference between tuning profiles of nonselective excitatory and inhibitory inputs, which we propose can be achieved through a differential circuit mediated by feedforward inhibition.
View details for DOI 10.1523/JNEUROSCI.3647-12.2012
View details for Web of Science ID 000312404700014
View details for PubMedID 23238722
Fine-tuning of pre-balanced excitation and inhibition during auditory cortical development
2010; 465 (7300): 927-U8
Functional receptive fields of neurons in sensory cortices undergo progressive refinement during development. Such refinement may be attributed to the pruning of non-optimal excitatory inputs, reshaping of the excitatory tuning profile through modifying the strengths of individual inputs, or strengthening of cortical inhibition. These models have not been directly tested because of the technical difficulties in assaying the spatiotemporal patterns of functional synaptic inputs during development. Here we apply in vivo whole-cell voltage-clamp recordings to the recipient layer 4 neurons in the rat primary auditory cortex (A1) to determine the developmental changes in the frequency-intensity tonal receptive fields (TRFs) of their excitatory and inhibitory inputs. Surprisingly, we observe co-tuned excitation and inhibition immediately after the onset of hearing, suggesting that a tripartite thalamocortical circuit with relatively strong feedforward inhibition is formed independently of auditory experience. The frequency ranges of tone-driven excitatory and inhibitory inputs first expand within a few days of the onset of hearing and then persist into adulthood. The latter phase is accompanied by a sharpening of the excitatory but not inhibitory frequency tuning profile, which results in relatively broader inhibitory tuning in adult A1 neurons. Thus the development of cortical synaptic TRFs after the onset of hearing is marked by a slight breakdown of previously formed excitation-inhibition balance. Our results suggest that functional refinement of cortical TRFs does not require a selective pruning of inputs, but may depend more on a fine adjustment of excitatory input strengths.
View details for DOI 10.1038/nature09079
View details for Web of Science ID 000278804500038
View details for PubMedID 20559386