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Dr. Helen Bateup , Department of Molecular & Cell Biology

Characterizing a Novel Subpopulation of Neurons in the Nucleus Accumbens Medial Shell

Abstract:

Neurons have traditionally been classified based on the neurotransmitters they release, but recent single cell RNA sequencing research has uncovered the abundance and diversity of neuropeptides expressed in neurons. One such study from the Bateup lab (Kramer et al, 2018) identified a novel subpopulation of dopamine neurons that contained mRNA for the neuropeptide Gastrin Releasing Peptide, Grp. Subsequent in situ hybridization demonstrated that mRNA for the Grp receptor, Grpr, was also expressed in the targeted brain region of these dopaminergic neurons, the striatum and nucleus accumbens medial shell (NAc MSh), suggesting Grp/Grpr may serve a purpose in functional signaling. 

Previous electrophysiology data from the lab indicates that these Grpr+ neurons in the NAc MSh are significantly more depolarized and have higher membrane resistance compared to neighboring medium spiny neurons (MSNs) in the region. Additionally, these neurons further depolarize and increase in excitability upon GRP wash-on. My goal in this project was to further characterize this novel subpopulation of cells in the NAc MSh that express Grpr. I did this by looking for other neuronal markers co-expressed in the Grpr+ neurons, examining their morphology through Sholl Analysis and their in vivo response to GRP injection, as well as developmental profiling. Preliminary in situ data indicates that these Grpr+ neurons are MSNs that express D2R, but not enkephalin. Morphology data is still forthcoming, but initial data suggests these neurons have fewer dendritic branches compared to Grpr- neighbors. Unilateral in vivo GRP injection resulted in a significantly larger amount of Grpr+ neurons becoming cFos+ compared to the uninjected hemisphere. Developmental profiling data suggests that in a GRPR:Cre mouse line, all striatal neurons may express GRPR during development, an idea that I’m pursuing further.

Through these experiments, I provide characterization of a novel Grpr-expressing subpopulation of neurons in the NAc MSh.

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Daniele Canzio , University of California San Francisco Weill Neurosciences

Investing the Role of Clustered Protocadherin Intracellular Domain Cleavage in Neuronal Self-Avoidance

Abstract:

As neurons arborize during development to create functional circuitry, it is crucial that neurites of individual neurons exhibit self-avoidance, which involves distinguishing themselves from other neurites. To generate a unique identity, a subset of protocadherins- a subfamily of cadherins- are stochastically expressed on the cell surface. Protocadherins on opposite cell membranes are involved in trans-homophilic binding, and if two protocadherin code sets are identical, they will repulse. The repulsion phenotype can be engineered, as seen in mice that transgenically overexpress protocadherin alpha c2 (pcdhac2) in the mouse olfactory system. Overexpression of a single protocadherin induces a “tiling” phenotype, where every neurite mistakenly recognizes its neighbor as identical- ultimately causing them to disperse. However, the mechanism of repulsion remains elusive. We believe that a core aspect of self-avoidance is rooted in the interactions of protocadherin intracellular domains (ICDs) after the trans-homophilic binding event. We hypothesize that ICDs are cleaved from the rest of the protein during the binding event, and the cleaved ICDs can then bind with other ICDs through cis-interactions, or downstream proteins of signaling pathways. In the common ICD (cICD) of the alpha protocadherin cluster, we recognize that multiple chains of lysines close to the C-terminus are potential active sites for events such as protocadherin oligomerization or downstream activity. To test their importance, we engineered a mutated version of protocadherin alpha c2 (pcdhac2mut), where the lysines are mutated to alanine. Pcdhac2mut is then trangenically overexpressed in the mouse olfactory system and transfected into K562 and Cath.-a-differentiated (CAD) cells. Data from our experiments in vivo and in vitro suggest that the lysine chains are important for protocadherin cleavage, and that cleavage is an important step of repulsion. 

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Richard Ivry , Department of Psychology, University of California, Berkeley (Helen Wills Neuroscience Institute) 

Implicit Motor Adaptation and Perceived Hand Position Without Proprioception: A Kinesthetic Error may be Derived from Efferent Signals

Abstract:

Our ability to produce goal-directed actions involves multiple learning processes. Among these, implicit adaptation is of utmost importance, keeping our sensorimotor system well-calibrated in response to changes in the body and environment. Implicit adaptation is assumed to be driven by a sensory prediction error, the difference between the predicted and actual sensory consequences of a movement. Whereas most models of implicit adaptation have focused on how visual information defines the sensory prediction error, we have recently proposed that this error signal is kinesthetic, the difference between the desired and perceived hand position, with adaptation serving to bring these two signals into alignment and restore optimal motor performance (Tsay et al., eLife, 2022). Here, we examined implicit adaptation and kinesthetic perception in rare individuals with severe proprioceptive deficits. We used an online visuomotor rotation task designed to isolate implicit adaptation while simultaneously probing the participants' perceived hand position. Specifically, participants used either a trackpad or mouse to move a computer cursor toward visual targets (see a video describing the task here: https://youtu.be/6eJ78sQsjF8). Participants made fast goal-directed movements across three blocks: a baseline block without visual feedback, a perturbation block with a 30° clamped visual feedback, and a washout block without visual feedback to measure aftereffects. Control participants exhibited robust implicit adaptation, that is, a gradual drift in hand angle away from the target, in the opposite direction to clamped visual feedback. Participants in both groups showed signatures of kinesthetic re-alignment, that is, an initial bias in perceived hand position towards the visual cursor and gradual shift back to the movement goal. The time course of both implicit adaptation and kinesthetic re-alignment was similar in the deafferented group, suggesting that proprioceptive afferents are not necessary for implicit adaptation and kinesthetic re-alignment. These results are problematic for both existing models, underscoring an important constraint on our understanding of sensorimotor learning: on one hand, the visuo-centric model can account for preserved implicit adaptation but not for kinesthetic changes; on the other hand, while our kinesthetic re-alignment model predicts both features, it predicts that magnitude of adaptation should be heightened in the deafferented group. These results motivated us to revise our thinking, recognizing that the original kinesthetic re-alignment model failed to incorporate a key input for perceived hand position--an efferent signal arising from the motor command of the expected hand position. We propose a revised kinesthetic re-alignment model in which a kinesthetic prediction error derived from efferent motor signals is sufficient to drive implicit adaptation and to re-align a biased percept of hand position with the movement goal.

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Mazen Kheirbek , University of California, San Francisco

The Effect of Chronic Silencing of Thalamic and Amygdalar Inputs to the Hippocampus

Abstract:

Avoidance behaviors in anxiogenic environments have been evolutionarily conserved for animal survival. Overgeneralization of avoidance behaviors, however, can oftentimes lead to potentially more harmful circumstances that may serve as precursors to many anxiety disorders. Many different brain regions contribute to generating appropriate behavioral responses in anxiogenic contexts, namely the ventral hippocampus (vHPC) as a mediator in avoidance behavior. We aimed to address what potential afferent inputs to vHPC support its function in mapping risky environments and coordinating avoidance behaviors. Previous work has shown that anxiety-like behaviors can be modulated by manipulating basolateral amygdala (BLA) inputs to vHPC. Additionally, recent work in our lab has presented preliminary data suggesting that acute inhibition of the paraventricular thalamus (PVT) input to vHPC can reduce anxiety-like behavior in animals. Considering BLA and PVT’s capacity to affect circuitry, we explore the impact of permanent silencing of PVT and BLA inputs to vHPC with tetanus toxin (TeLC).

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Richard M. Harland , Department of Molecular & Cell Biology

Electrophysiological Properties of Ganglia and Their Mechanisms  of Action in the Jellyfish Cassiopea xamachana

Abstract:

Previous work has shown that the upside-down jellyfish Cassiopea xamachana exhibits sleep-like behaviors, such as latency to arousal and decreased activity levels. However, the underlying cellular mechanism behind these behaviors is yet to be fully understood. In this study, we used extracellular electrophysiology recordings to investigate how neuronal signals may control these behaviors. Spontaneous action potentials from the ganglia, which are nerve clusters within the decentralized nervous system of these jellyfish, were recorded in five conditions: light, dark, lidocaine, melatonin, and menthol. Statistical analyses showed that when moving ganglia from light to dark environments, there were near-immediate and significant reductions in action potential frequency. This supports the existence of photosensitive neurons which play a role in controlling behaviors observed in Cassiopea xamachana. Treatment with lidocaine, a local anesthetic, almost completely silenced ganglia. With melatonin-treated ganglia, we found that action potential frequency patterns were similar to recordings from ganglia in the dark environment despite being in the light, indicating activation of melatonin receptors. Menthol treatment also showed reduced firing in the light, representing reduced activity levels associated with TRP channel activation. Aside from the treatment experiments, single ganglion recordings from dual ganglia tissue were also conducted to see if there were changes in neuronal signals when ganglia remained connected to another member of the neural net. From these recordings, we observed a hyperpolarizing waveform which may be involved in silencing other ganglia during whole-body muscle contractions to avoid a staggered contraction wave. Overall, these findings shed new light on the cellular mechanisms which underly the regulation of sleep-like behaviors in an organism with a decentralized nervous system, potentially providing insight into the mechanisms and function of sleep in other animals. 

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Noah Whiteman , UC Berkeley

Developing a Genome Annotation Pipeline for the Newly Sequenced B. Philenor’s Genome Assembly

Abstract:

The California Pipevine Swallowtail Butterfly (Battus philenor hiresuta) occurs only where its host plant (Aristolochia) exists in north-central California. It is a disjunct population from the far more widespread Pipevine Swallowtail Butterfly (B. philenor) found throughout the southern and southeast U.S. (Fordyce 2000; Fordyce and Agrawal 2001). Furthermore, the California Pipevine Swallowtail differs from the Pipevine Swallowtail butterfly in that its larvae feed on a Aristolochia host vine (Fordyce and Agrawal 2001). Larvae of the California B. philenor butterfly sequester toxic alkaloids (aristolochic acids) from their Aristolochia host plants, rendering larvae and adults unpalatable to a broad range of predators (Dimarco 2012). In this project, we developed a bioinformatic pipeline to generate a genome annotation for the newly sequenced genome assembly of B. philenor hirsuta.

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Doris Tsao , Department of Molecular & Cell Biology

Face and Object Representations in IT Cortex

Abstract:

Faces are ubiquitous in social interactions, and it is thus evolutionarily advantageous to be able to accurately recognize different types of facial features. Primate brains contain an array of specialized machinery, called the face patch system, located in the inferotemporal (IT) cortex to support facial recognition, which is composed of neuronal populations that selectively fire in response to faces present in visual stimuli. Recent studies have also shown that other neural populations in IT cortex parameterize non-face objects. However, it is largely unknown whether there exists a face detection step prior to face patches, or if face-selective neurons are tuned to axes in a general latent space that is shared between faces and objects. This project elucidates the role of face patches in visual processing by examining the effect of contextual information on responses of both artificial and biological face-selective units. We analyzed Neuropixels recordings in face patches while showing a variety of faces and objects to map out axes in object space that each face-selective cell is tuned along. Interestingly, we found that axes mapped from face stimuli exhibited larger variance than those mapped from object stimuli, and that objects with similar features in latent space evoked distinct responses from face patches. Furthermore, we designed a novel set of stimuli containing faces superimposed on a variety of natural scenes, which can also be parameterized in a latent space by their semantic contexts through a deep neural network. Analyzing recordings from face patches with this stimulus set showed that face patch responses are correlated with the natural scene context of faces. Finally, we show that we can decode both face and context information from neural population responses. Taken together, our results provide a better understanding of neural representations of faces and objects in IT cortex.

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Vikaas Sohal , UCSF

Mapping Long-Range Interneurons Involved in Aversive Stimuli Avoidance Behavior with Fluorescence Microscopy

Abstract:

Faces are ubiquitous in social interactions, and it is thus evolutionarily advantageous to be able to accurately recognize different types of facial features. Primate brains contain an array of specialized machinery, called the face patch system, located in the inferotemporal (IT) cortex to support facial recognition, which is composed of neuronal populations that selectively fire in response to faces present in visual stimuli. Recent studies have also shown that other neural populations in IT cortex parameterize non-face objects. However, it is largely unknown whether there exists a face detection step prior to face patches, or if face-selective neurons are tuned to axes in a general latent space that is shared between faces and objects. This project elucidates the role of face patches in visual processing by examining the effect of contextual information on responses of both artificial and biological face-selective units. We analyzed Neuropixels recordings in face patches while showing a variety of faces and objects to map out axes in object space that each face-selective cell is tuned along. Interestingly, we found that axes mapped from face stimuli exhibited larger variance than those mapped from object stimuli, and that objects with similar features in latent space evoked distinct responses from face patches. Furthermore, we designed a novel set of stimuli containing faces superimposed on a variety of natural scenes, which can also be parameterized in a latent space by their semantic contexts through a deep neural network. Analyzing recordings from face patches with this stimulus set showed that face patch responses are correlated with the natural scene context of faces. Finally, we show that we can decode both face and context information from neural population responses. Taken together, our results provide a better understanding of neural representations of faces and objects in IT cortex.

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Gary D. Richards , A.A. Dugoni School of Dentistry, University of the Pacific

Factors Underlying Bony Lesions in a Central California Prehistoric Population: Causative or Reactive Responses to Inflammation and Immune System Activation

Abstract:

​​Native North Americans show high frequencies of rheumatoid arthritis (RA) but lack HLA alleles classically associated with a genetic predisposition. Whether this susceptibility to RA was present in prehistoric populations is unknown, as it may have arisen in the 1800s as a protective mechanism against Mycobacterium tuberculosis infection. Here we evaluate immune system pathways that link an expression of a rheumatoid-like arthritis with an M. tuberculosis infection in prehistoric California. 

In a sample of 8564 prehistoric California individuals, 2570 showed bone pathology.  Of the latter, six showed evidence of M. tuberculosis infection.  These individuals derive from the Hotchkiss Mound (CCo-138), a prehistoric Central California shellmound.  In this population, 318 individuals have bone pathology, with 68.24% possessing joint lesions.  We also compiled comparative paleoepidemiological profiles for two other shellmound populations.

The incidence of joint lesions at CCo-138 is like other shellmound populations.  However, the CCo-138 population expresses a highly destructive, symmetrical polyarticular arthritis, unique to this locality. The pattern of joint destruction resembles RA.  However, extensive destruction of vertebral/rib synovial joints, related processes, and associated periosteal bone deposits appears like osteoarthritis. Individuals with M. tuberculosis express extensive erosive lesions of the mid thoracic/upper lumbar vertebrae but lack a periosteal response or synovial joint involvement. 

This co-occurrence of M. tuberculosis and a uniquely patterned joint disease is unique in prehistoric California.  We suggest that individuals were infected with the tuberculosis bacterium early in life. Since the presence of M. tuberculosis is confirmed at CCo-138 for >500 years, we suggest that there was selection for individuals with a genetic predisposition to RA or a rheumatoid-like arthritis. In later age groups, T cell exhaustion or alteration of antigen gene expression profiles results in the reactivation of the tuberculosis bacterium. The reduction in T cells would ameliorate the effects of TNF on the joints. However, the reactivation of the tuberculosis bacterium would then potentially drive rapid and severe destruction of the joints observed in this sample.

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Randy W. Schekman , Li Ka Shing

Paralog Specific Functions of Rab27a and Rab27b in Exosome Secretion

Abstract:

Extracellular vesicles (EVs) are membrane-bound compartments that are exported out of cells. There are two major subpopulations of EVs: microvesicles and exosomes. Exosomes have garnered particular interest in the scientific community due to recent studies suggesting a role for exosomes in intercellular communication in both normal and disease states.Additionally, exosomes can be utilized as diagnostic biomarkers for a variety of disease conditions. Despite broad interest in exosomes, little is known about how their release is regulated (Hessvik and Llorente, 2017). Rab27a and Rab27b are two very closely related proteins that regulate different steps of exosome secretion. How such similar proteins can control separate steps of this pathway is not well understood. My proposed research aims to characterize the distinct mechanisms by which Rab27a and Rab27b control exosome secretion using both genetic and biochemical approaches. Obtaining a more comprehensive understanding of how Rab27a and Rab27b regulate exosome secretion will provide insight into how exosomes contribute to disease progression.

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Stephan Lammel , Department of Molecular & Cell Biology

Heterogeneity in Striatal Acetylcholine and Dopamine Dynamics Underlying Conditioned Behavior

Abstract:

Research shows that the nucleus accumbens (NAc) is critical for mediating the influence of contexts on cue-responding. The NAc contains acetylcholine-producing neurons that locally modulate dopamine (DA) release, yet the interplay between acetylcholine (ACh)and DA in the NAc to regulate behavior is not understood. We first examined how local ACh release in the NAc was related to rewarding, aversive, and neutral events to map how ACh release corresponds to stimuli of differing valence. We expressed the fluorescent biosensor GRAB-gACh4h in the NAc to record ACh in real-time as mice behaved with fiber photometry. We found a gradient of reward and aversion encoding throughout the NAc as we previously found for DA release. To better understand this, we expressed both GRAB-gACh4h and GRAB-rDA3m in the NAc to simultaneously record ACh and DA release. ACh release preceded DA release and this relationship was heterogeneous throughout the NAc, with distinct timescales for ACh and DA in different NAc subregions. To understand if this interplay affected the role of these modulators in behavior, we trained mice in a Pavlovian reward-seeking task, where distinct sounds were either paired with reward or not. In the medial NAc, ACh and DA responses exhibited ramping responses that began at cue onset, reflecting the mice’s anticipation of reward delivery. However in the lateral NAc, ACh release was steady and reflected the value of each cue; DA release was brief and only evident at the time of the rewarded cue. Collectively, we reveal a novel source of heterogeneity in the ACh dynamics and in the interplay between ACh and DA release throughout the NAc. Given that neuroadaptations in the NAc underlie a number of maladaptive features of psychiatric illnesses, understanding this heterogeneity can inspire novel approaches to developing treatments.

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William J Jagust , Barker Hall - University of California, Berkeley

Age-differences in Behavioral and Neural Effects of Prior Knowledge on Memory

Abstract:

Prior knowledge influences memory in two distinct ways: a superior memory performance for knowledge-congruent information and more false memories for knowledge-congruent information. We investigated whether these effects persist in older people and explored the neural mechanisms using functional magnetic resonance imaging (fMRI). Twenty older (aged 60-91 years) and 17 young participants (aged 19–35 years) were presented with images depicting an object in a scene in the scanner, where half of the objects were likely to be in the scene (congruent) and half were unlikely (incongruent). Approximately 50 minutes after the presentation, they were given a surprise recognition test outside the scanner to determine if they remembered the pictures. Mixed effects logistic regressions examined the effect of age, congruency, and their interactions on memory. FMRI analysis focused on high-confidence hit and high-confidence false alarm contrasts in the medial temporal lobe (MTL) and ventral medial prefrontal cortex (vmPFC) for congruent versus incongruent conditions. Behaviorally, we found that congruent object-scene pairs had both higher hit rates (p=0.007) and higher false alarm rates (p=0.003) than incongruent ones. FMRI analysis revealed stronger activation in the right parahippocampal region in young adults compared to older adults, independent of congruency, and stronger activation in the orbital middle frontal region for congruent false alarms than incongruent ones, independent of age. The behavioral results suggest that prior knowledge both enhances true memory but also induces more false memories. FMRI findings show vmPFC’s over-activation for knowledge-congruent false alarms, suggesting its involvement in gist-based, generalized memory processing leads to schema-consistent memory errors. Finally, the age-related reduction in parahippocampal activation aligns with prior research on age-related disruptions in MTL and may explain the poorer memory performance in older adults compared to young adults across conditions.

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Miaw-Sheue Tsai , Lawrence Berkeley National Laboratory

Cloning, Expressing, and Purifying DNA Damage Repair Protein Kinases in Human cells using the BacMam Expression System

Abstract:

DNA-PKcs, ATM, and ATR-ATRIP are three major protein kinases that play a role in response to DNA damage, especially DNA double strand breaks (DSB) and replication stress.  These kinases, once activated, phosphorylate key protein targets to promote efficient DNA repair pathways. Obtaining these functional protein kinases is challenging because of their large protein size and purifying them in insect cell lines is not feasible because of poor or no expression, or lack of activity. To study how these kinases activate and coordinate post-translational modifications of DNA damage response, the BacMam system is being used to determine its potential in expressing active protein kinases in human cells. The BacMam (Baculovirus-Mammalian) system uses a baculovirus as a vector to deliver genes of interest into mammalian cells. In this project so far, ATR-ATRIP and ATM were subcloned into the BacMam shuttle vector, while it is more difficult with the larger DNA-PKcs, as all trials so far have resulted in low PCR yields. Both ATR/ATRIP and ATM protein kinases were successfully expressed and purified from human cells. Moreover, purified ATR/ATRIP is an active kinase (that phosphorylates RPA). Thus, the BacMam system has been a success to produce active ATR/ATRIP. 

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Richard Harland , Department of Molecular & Cell Biology

Perturbation of Cholinergic Circuitry and MITF in the Jellyfish Cassiopea xamachana

Abstract:

The upside-down jellyfish, Cassiopea xamachana, is the first Cnidarian to have a characterized sleep-like state despite a lack of a centralized nervous system. The rhopalia of Cassiopea are bulb-like structures on the edge of the bell that sense light and control pulsing activity, and initially develop as Cassiopea transitions from the polyp to ephyra stages. The rhopalia contain melanocytes that express melanin characterized by a visible brown spot on the rhopalia. RNAi was used to knockdown the melanocyte-inducing-transcription-factor (MITF) gene in Cassiopea polyps which were then induced to develop into ephyrae to understand the role of melanocytes in Cassiopea development. I found that ephyrae treated with RNAi may develop faster, but with lower levels of melanin, suggesting a regulatory role of MITF in development. 

        One of the characteristics of sleep that Cassiopea display is a latency to arousal (LTA) effect when exposed to a dark condition after being in the light (L/D) characterized by an increase in interpulse intervals (IPI) after a short delay. Previous pharmacological experiments conducted in the lab studied the effects of inhibiting nicotinic acetylcholine receptors (nAChR) and found that D-tubocurarine (DTC) reduced Cassiopea pulse rate. I administered DTC in conjunction with L/D tests to understand the effects of nAChRs on sleep. L/D tests with the inhibition of muscarinic acetylcholine receptors (mAChR) using atropine were also performed to compare the effects of inhibiting mAChRs versus nAChRs. Cassiopea under the inhibition of DTC displayed a longer time to respond to changes in light condition suggesting the inhibition of nAChR places the jellyfish into a deeper sleep state. Obtaining a greater understanding of the acetylcholine circuitry and the development of the rhopalia lays a better foundation for Cassiopea to be utilized as a model organism for sleep and neurobiological research.

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Hillel Adesnik , Department of Molecular & Cell Biology

Behavioral State Impacts Neural but not Behavioral Response to Visual Stimuli

Abstract:

Deciphering the neural circuits that encode visual perception has proven to be an elusive goal. Understanding how internal states influence the encoding of visual perceptions and subsequent behavioral responses may further elucidate the neural circuits involved. Pupil sizes have been shown to correlate to certain neuromodulatory systems that broadly alter brain states. Arousal, as measured by pupil dilation, has been shown to suppress neural “noise”, increasing the salience of stimulus-evoked neural activity, and enhance visual encoding. Thus, we hypothesized that, by enhancing the relevance of visual stimuli, arousal would increase the likelihood of its successful interpretation and improve the downstream behavioral response. To test this, we trained mice to detect a drifting grating at different contrasts to receive a water reward. We recorded the pupils of mice and the neural activity in their visual cortex while they performed the visual contrast detection task. Interestingly, our results show that, for mice that are actively engaged in a task, i.e., interpreting stimuli to receive a reward, while behavioral state does influence neural response amplitude, it does not significantly impact noise correlations or downstream behavioral response. This suggests that behavioral state may interact with other internal states to differentially modulate activity, but it does not have a significant impact on perception of stimuli in actively engaged mice.

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Hillel Adesnik , Department of Molecular & Cell Biology

Behavioral State Impacts Neural but not Behavioral Response to Visual Stimuli

Abstract:

Deciphering the neural circuits that encode visual perception has proven to be an elusive goal. Understanding how internal states influence the encoding of visual perceptions and subsequent behavioral responses may further elucidate the neural circuits involved. Pupil sizes have been shown to correlate to certain neuromodulatory systems that broadly alter brain states. Arousal, as measured by pupil dilation, has been shown to suppress neural “noise”, increasing the salience of stimulus-evoked neural activity, and enhance visual encoding. Thus, we hypothesized that, by enhancing the relevance of visual stimuli, arousal would increase the likelihood of its successful interpretation and improve the downstream behavioral response. To test this, we trained mice to detect a drifting grating at different contrasts to receive a water reward. We recorded the pupils of mice and the neural activity in their visual cortex while they performed the visual contrast detection task. Interestingly, our results show that, for mice that are actively engaged in a task, i.e., interpreting stimuli to receive a reward, while behavioral state does influence neural response amplitude, it does not significantly impact noise correlations or downstream behavioral response. This suggests that behavioral state may interact with other internal states to differentially modulate activity, but it does not have a significant impact on perception of stimuli in actively engaged mice.

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Lea T Grinberg , Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco

Selective vulnerability of the Locus Coeruleus in Distinct Tauopathies

Abstract:

Tauopathies are the most common type of neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. Tauopathies can present with a range of clinical manifestations such as cognitive/behavioral-disorders, movement disorders, language disorders and amnestic symptoms. Once of the most prevalent tauopathies is Alzheimer's Disease (AD) affecting about 1 in 9 people age 65 and older. 

The brainstem nucleus of the Locus Coeruleus (LC) is one of the first brain structures to accumulate hyperphosphorylated tau inclusions in AD. In addition to AD, the LC is also susceptible to tau aggregation in select other tauopathies and even normal aging. 

We used well-characterized human postmortem tissue from healthy elderly controls and patients with pure AD/Late-onset AD (LOAD), Early-onset-AD, Logopenic, and Posterior Cortical Atrophy (PCA) to create and compare quantitative, multidimensional maps capturing the pattern of the selective neuronal vulnerability of the LC for these tauopathies. This work will hopefully help map the progression and mechanism of different tauopathies clinical characteristics, assisting in the identification and strengthening of therapeutic targets.

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Andrew Dillin , Department of Molecular & Cell Biology, University of California, Berkeley, and Howard Hughes Medical Institute

The Effects of the Rearrangement of the  Extracellular Matrix on Longevity in C.elegans

Abstract:

Organisms have developed intricate strategies to regulate the balance of proteins within cells. One important example is the mitochondrial unfolded protein response (UPRmt), a mechanism that has been linked to various illnesses and the aging phenomenon. Previous CRISPR based knockout screens performed by other members of the lab have found that the hyaluronidase, Transmembrane Protein 2 (TMEM2), is an important modulator of cellular protein homeostasis. TMEM2 triggers extracellular matrix degradation; the extracellular matrix (ECM) is a web of complex fibrous proteins such as collagens, glycoproteins, and proteoglycans (a combination of glycosaminoglycans along with core proteins). We confirmed that TMEM2 causes overall remodeling of the ECM in worms. When organisms age, their cellular ability to regulate protein homeostasis declines, resulting in decreased longevity. This dysfunction can activate multiple organelle stress response pathways. These pathways stimulate downstream cascades aimed at restoring homeostasis, and cells recover from the previous stress-induced decrease in longevity. Interestingly, several stress response pathways were found up-regulated in TMEM2 overexpressing (TMEM2-OE) worms, including mitochondrial unfolded protein responses and oxidative stress responses. Expression of TMEM2 in specific tissues revealed varying degrees of increased longevity, with intestine-specific promotion showing most prominent longevity. Lastly, ongoing experiments are being completed to determine if the transcription factor responsible for mediating the oxidative stress response, skn-1, is necessary for promoting longevity.

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Qili Liu , University of California, San Francisco

Social Isolation Induces Sugar Preference In Drosophila

Abstract:

In a post-pandemic world impinged by rifts in social networks and marked by indulgence in 21st technology and work culture, day-to-day social isolation is on the rise, making it critical that we understand its effects on physical and mental health. However, little is known about how and why loneliness impacts food choice. To study this question, we examined the very dystopia we must avoid: a world of atomized individuals. Using Drosophila fruit fly as a model system, we investigated the phenotype and neural circuit of a lack of social experiences on food choice between protein and sugar. Our data reveals a robust sugar preference after social isolation that varied with the length of the isolation period and persisted even after protein starvation. Furthermore, we reveal candidate pathways in the social isolation-mediated sugar preference circuit. Activating the P2 neuron (previously identified as a neural detector of social experiences) increased sugar preference in the socially enriched group (8-10 flies). We then conducted an RNAi screen of dopaminergic neuron clusters composing the non-PAM TH-Gal4 line. We identified that inhibiting the TH-C’-Gal4 also increased the sugar preference of the socially enriched group. Together, we demonstrate a robust sugar preference following social isolation and identify candidates in the pathway mediating the neural circuit.

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Richard Ivry , Department of Psychology

Deriving Profiles of Developmental Dyslexia from a Battery of Online Tasks

Abstract:

While the defining feature of developmental dyslexia (DD) centers on difficulty in reading, there is considerable variability in the degree to which individuals with DD exhibit learning impairments in domains not directly related to reading. Moreover, the literature suggests that learning impairments observed in DD may be manifested in a wide range of domains, many of which are not directly related to reading. Our goal is to account for this variance by creating profiles of DD. We are administering a series of online tasks that measure practice effects for arithmetic, motor sequencing, and statistical learning. For each task, a measure of learning will be obtained, and, using a machine-learning approach (e.g., Finite Mixture Models), we will extract clusters that characterize performance across multiple domains. This approach will allow us to: i) Identify prominent profiles of DD, ii) Characterize learning disabilities of subtypes of DD, and iii) Empirically assess different hypotheses put forth to account for cognitive deficits underlying DD across different task domains (e.g., procedural learning).

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Miaw-Sheue Tsai  , Lawrence Berkeley National Laboratory 

“Cloning, Expressing, and Purifying DNA Damage Repair Protein Kinases in Human cells using the BacMam Expression System” 

Abstract:

DNA-PKcs, ATM, and ATR-ATRIP are three major protein kinases that play a role in response to DNA damage, especially DNA double strand breaks (DSB) and replication stress. These kinases, once activated, phosphorylate key protein targets to promote efficient DNA repair pathways. Obtaining these functional protein kinases is challenging because of their large protein size and purifying them in insect cell lines is not feasible because of poor or no expression, or lack of activity. To study how these kinases activate and coordinate post-translational modifications of DNA damage response, the BacMam system is being used to determine its potential in expressing active protein kinases in human cells. The BacMam (Baculovirus-Mammalian) system uses a baculovirus as a vector to deliver genes of interest into mammalian cells. In this project so far, ATR-ATRIP and ATM were subcloned into the BacMam shuttle vector, while it is more difficult with the larger DNA-PKcs, as all trials so far have resulted in low PCR yields. Both ATR/ATRIP and ATM protein kinases were successfully expressed and purified from human cells. Moreover, purified ATR/ATRIP is an active kinase (that phosphorylates RPA). Thus, the BacMam system has been a success to produce active ATR/ATRIP.