• Action recognition using Natural Action Structures

      Zhu, Xiaoyuan; Yang, Zhiyong; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology; Department of Ophthalmology (2012-07-16)
    • Balanced Dopamine Is Critical for Pattern Completion during Associative Memory Recall

      Li, Fei; Wang, Lei Phillip; Shen, Xiaoming; Tsien, Joe Z.; Brain & Behavior Discovery Institute (2010-10-27)
      Pattern completion, the ability to retrieve complete memories initiated by partial cues, is a critical feature of the memory process. However, little is known regarding the molecular and cellular mechanisms underlying this process. To study the role of dopamine in memory recall, we have analyzed dopamine transporter heterozygous knockout mice (DAT+/-), and found that while these mice possess normal learning, consolidation, and memory recall under full cue conditions, they exhibit specific deficits in pattern completion under partial cue condition. This form of memory recall deficit in the dopamine transporter heterozygous knockout mice can be reversed by a low dose of the dopamine antagonist haloperidol, further confirming that the inability to retrieve memory patterns is a result of dopamine imbalance. Therefore, our results reveal that a delicate control of the brain's dopamine level is critical for pattern completion during associative memory recall.
    • A computational model of posterior parietal circuits during decision making and sequential planning

      Li, Yuhui; Cui, He; Brain & Behavior Discovery Institute; Department of Psychiatry and Health Behavior (2012-07-16)
    • Conditional knockout of NMDA receptors in dopamine neurons prevents nicotine-conditioned place preference.

      Wang, Lei Phillip; Li, Fei; Shen, Xiaoming; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology (2010-01-11)
      Nicotine from smoking tobacco produces one of the most common forms of addictive behavior and has major societal and health consequences. It is known that nicotine triggers tobacco addiction by activating nicotine acetylcholine receptors (nAChRs) in the midbrain dopaminergic reward system, primarily via the ventral tegmental area. Heterogeneity of cell populations in the region has made it difficult for pharmacology-based analyses to precisely assess the functional significance of glutamatergic inputs to dopamine neurons in nicotine addiction. By generating dopamine neuron-specific NR1 knockout mice using cre/loxP-mediated method, we demonstrate that genetic inactivation of the NMDA receptors in ventral tegmental area dopamine neurons selectively prevents nicotine-conditioned place preference. Interestingly, the mutant mice exhibit normal performances in the conditioned place aversion induced by aversive air puffs. Therefore, this selective effect on addictive drug-induced reinforcement behavior suggests that NMDA receptors in the dopamine neurons are critical for the development of nicotine addiction.
    • Conjunctive Processing of Locomotor Signals by the Ventral Tegmental Area Neuronal Population

      Wang, Dong V.; Tsien, Joe Z.; Brain & Behavior Discovery Institute (2011-01-27)
      The ventral tegmental area (VTA) plays an essential role in reward and motivation. How the dopamine (DA) and non-DA neurons in the VTA engage in motivation-based locomotor behaviors is not well understood. We recorded activity of putative DA and non-DA neurons simultaneously in the VTA of awake mice engaged in motivated voluntary movements such as wheel running. Our results revealed that VTA non-DA neurons exhibited significant rhythmic activity that was correlated with the animal's running rhythms. Activity of putative DA neurons also correlated with the movement behavior, but to a lesser degree. More importantly, putative DA neurons exhibited significant burst activation at both onset and offset of voluntary movements. These findings suggest that VTA DA and non-DA neurons conjunctively process locomotor-related motivational signals that are associated with movement initiation, maintenance and termination.
    • Convergent Processing of Both Positive and Negative Motivational Signals by the VTA Dopamine Neuronal Populations

      Wang, Dong V.; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology (2011-02-15)
      Dopamine neurons in the ventral tegmental area (VTA) have been traditionally studied for their roles in reward-related motivation or drug addiction. Here we study how the VTA dopamine neuron population may process fearful and negative experiences as well as reward information in freely behaving mice. Using multi-tetrode recording, we find that up to 89% of the putative dopamine neurons in the VTA exhibit significant activation in response to the conditioned tone that predict food reward, while the same dopamine neuron population also respond to the fearful experiences such as free fall and shake events. The majority of these VTA putative dopamine neurons exhibit suppression and offset-rebound excitation, whereas ~25% of the recorded putative dopamine neurons show excitation by the fearful events. Importantly, VTA putative dopamine neurons exhibit parametric encoding properties: their firing change durations are proportional to the fearful event durations. In addition, we demonstrate that the contextual information is crucial for these neurons to respectively elicit positive or negative motivational responses by the same conditioned tone. Taken together, our findings suggest that VTA dopamine neurons may employ the convergent encoding strategy for processing both positive and negative experiences, intimately integrating with cues and environmental context.
    • Different Neuroplasticity for Task Targets and Distractors

      Spingath, Elsie Y.; Kang, Hyun Sug; Plummer, Thane; Blake, David T.; Brain & Behavior Discovery Institute; Graduate Program in Neuroscience; Department of Neurology (2011-01-31)
      Adult learning-induced sensory cortex plasticity results in enhanced action potential rates in neurons that have the most relevant information for the task, or those that respond strongly to one sensory stimulus but weakly to its comparison stimulus. Current theories suggest this plasticity is caused when target stimulus evoked activity is enhanced by reward signals from neuromodulatory nuclei. Prior work has found evidence suggestive of nonselective enhancement of neural responses, and suppression of responses to task distractors, but the differences in these effects between detection and discrimination have not been directly tested. Using cortical implants, we defined physiological responses in macaque somatosensory cortex during serial, matched, detection and discrimination tasks. Nonselective increases in neural responsiveness were observed during detection learning. Suppression of responses to task distractors was observed during discrimination learning, and this suppression was specific to cortical locations that sampled responses to the task distractor before learning. Changes in receptive field size were measured as the area of skin that had a significant response to a constant magnitude stimulus, and these areal changes paralleled changes in responsiveness. From before detection learning until after discrimination learning, the enduring changes were selective suppression of cortical locations responsive to task distractors, and nonselective enhancement of responsiveness at cortical locations selective for target and control skin sites. A comparison of observations in prior studies with the observed plasticity effects suggests that the non-selective response enhancement and selective suppression suffice to explain known plasticity phenomena in simple spatial tasks. This work suggests that differential responsiveness to task targets and distractors in primary sensory cortex for a simple spatial detection and discrimination task arise from nonselective increases in response over a broad cortical locus that includes the representation of the task target, and selective suppression of responses to the task distractor within this locus.
    • Differential Consolidation and Pattern Reverberations within Episodic

      Osan, Remus; Chen, Guifen; Feng, Ruiben; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology (2011-02-15)
      One hallmark feature of consolidation of episodic memory is that only a fraction
    • Dorsal parietal area 5 only encodes the immediate reach in sequential arm movement

      Li, Yuhui; Cui, He; Brain & Behavior Discovery Institute; Department of Psychiatry and Health Behavior (2012-07-16)
    • Encoding of emotion-paired spatial stimuli in the rodent hippocampus

      Nalloor, Rebecca Ipe; Bunting, Kristopher M.; Vazdarjanova, Almira; Brain & Behavior Discovery Institute; Department of Neurology (2012-06-14)
      Rats can acquire the cognitive component of CS-US associations between sensory and aversive stimuli without a functional basolateral amygdala (BLA). Thus, other brain regions should support such associations. Some septal/dorsal CA1 (dCA1) neurons respond to both spatial stimuli and footshock, suggesting that dCA1 could be one such region. We report that, in both dorsal and ventral hippocampus, different neuronal ensembles express immediate-early genes (IEGs) when a place is experienced alone vs. when it is associated with foot shock. We assessed changes in the size and overlap of hippocampal neuronal ensembles activated by two behavioral events using a cellular imaging method, Arc/Homer1a catFISH. The control group (A-A) experienced the same place twice, while the experimental group (A-CFC) received the same training plus two foot shocks during the second event. During fear conditioning, A-CFC, compared to A-A, rats had a smaller ensemble size in dCA3, dCA1, and vCA3, but not vCA1. Additionally, A-CFC rats had a lower overlap score in dCA1 and vCA3. Locomotion did not correlate with ensemble size. Importantly, foot shocks delivered in a training paradigm that prevents establishing shock-context associations, did not induce significant Arc expression, rejecting the possibility that the observed changes in ensemble size and composition simply reflect experiencing a foot shock. Combined with data that Arc is necessary for lasting synaptic plasticity and long-term memory, the data suggests that Arc/H1a+ hippocampal neuronal ensembles encode aspects of fear conditioning beyond space and time. Rats, like humans, may use the hippocampus to create integrated episodic-like memory during fear conditioning.
    • Forebrain NR2B Overexpression Facilitating the Prefrontal Cortex Long-Term Potentiation and Enhancing Working Memory Function in Mice

      Cui, Yihui; Jin, Jing; Zhang, Xuliang; Xu, Hao; Yang, Liguo; Du, Dan; Zeng, Qingwen; Tsien, Joe Z.; Yu, Huiting; Cao, Xiaohua; et al. (2011-05-31)
      Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.
    • Fragment-Based Learning of Visual Object Categories in Non-Human Primates

      Kromrey, Sarah; Maestri, Matthew; Hauffen, Karin; Bart, Evgeniy; Hegéd, Jay; Brain & Behavior Discovery Institute; Vision Discovery Institute; Department of Ophthalmology (2010-11-24)
      When we perceive a visual object, we implicitly or explicitly associate it with an object category we know. Recent research has shown that the visual system can use local, informative image fragments of a given object, rather than the whole object, to classify it into a familiar category. We have previously reported, using human psychophysical studies, that when subjects learn new object categories using whole objects, they incidentally learn informative fragments, even when not required to do so. However, the neuronal mechanisms by which we acquire and use informative fragments, as well as category knowledge itself, have remained unclear. Here we describe the methods by which we adapted the relevant human psychophysical methods to awake, behaving monkeys and replicated key previous psychophysical results. This establishes awake, behaving monkeys as a useful system for future neurophysiological studies not only of informative fragments in particular, but also of object categorization and category learning in general.
    • Genetic enhancement of memory and long-term potentiation but not CA1 long-term depression in NR2B transgenic rats.

      Wang, Deheng; Cui, Zhenzhong; Zeng, Qingwen; Kuang, Hui; Wang, Lei Phillip; Tsien, Joe Z.; Cao, Xiaohua; Brain & Behavior Discovery Institute; Department of Neurology (2009-10-19)
      One major theory in learning and memory posits that the NR2B gene is a universal genetic factor that acts as rate-limiting molecule in controlling the optimal NMDA receptor's coincidence-detection property and subsequent learning and memory function across multiple animal species. If so, can memory function be enhanced via transgenic overexpression of NR2B in another species other than the previously reported mouse species? To examine these crucial issues, we generated transgenic rats in which NR2B is overexpressed in the cortex and hippocampus and investigated the role of NR2B gene in NMDA receptor-mediated synaptic plasticity and memory functions by combining electrophysiological technique with behavioral measurements. We found that overexpression of the NR2B subunit had no effect on CA1-LTD, but rather resulted in enhanced CA1-LTP and improved memory performances in novel object recognition test, spatial water maze, and delayed-to-nonmatch working memory test. Our slices recordings using NR2A- and NR2B-selective antagonists further demonstrate that the larger LTP in transgenic hippocampal slices was due to contribution from the increased NR2B-containing NMDARs. Therefore, our genetic experiments suggest that NR2B at CA1 synapses is not designated as a rate-limiting factor for the induction of long-term synaptic depression, but rather plays a crucial role in initiating the synaptic potentiation. Moreover, our studies provide strong evidence that the NR2B subunit represents a universal rate-limiting molecule for gating NMDA receptor's optimal coincidence-detection property and for enhancing memory function in adulthood across multiple mammalian species.
    • Genetic Overexpression of NR2B Subunit Enhances Social Recognition Memory for Different Strains and Species

      Jacobs, Stephanie A.; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology (2012-04-27)
      The ability to learn and remember conspecifics is essential for the establishment and maintenance of social groups. Many animals, including humans, primates and rodents, depend on stable social relationships for survival. Social learning and social recognition have become emerging areas of interest for neuroscientists but are still not well understood. It has been established that several hormones play a role in the modulation of social recognition including estrogen, oxytocin and arginine vasopression. Relatively few studies have investigated how social recognition might be improved or enhanced. In this study, we investigate the role of the NMDA receptor in social recognition memory, specifically the consequences of altering the ratio of the NR2Bâ ¶NR2A subunits in the forebrain regions in social behavior. We produced transgenic mice in which the NR2B subunit of the NMDA receptor was overexpressed postnatally in the excitatory neurons of the forebrain areas including the cortex, amygdala and hippocampus. We investigated the ability of both our transgenic animals and their wild-type littermate to learn and remember juvenile conspecifics using both 1-hr and 24-hr memory tests. Our experiments show that the wild-type animals and NR2B transgenic mice preformed similarly in the 1-hr test. However, transgenic mice showed better performances in 24-hr tests of recognizing animals of a different strain or animals of a different species. We conclude that NR2B overexpression in the forebrain enhances social recognition memory for different strains and animal species.
    • A Hierarchical Probabilistic Model for Rapid Object Categorization in Natural Scenes

      He, Xiaofu; Yang, Zhiyong; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Ophthalmology; Department of Neurology (2011-05-25)
      Humans can categorize objects in complex natural scenes within 100â 150 ms. This amazing ability of rapid categorization has motivated many computational models. Most of these models require extensive training to obtain a decision boundary in a very high dimensional (e.g., â ¼6,000 in a leading model) feature space and often categorize objects in natural scenes by categorizing the context that co-occurs with objects when objects do not occupy large portions of the scenes. It is thus unclear how humans achieve rapid scene categorization.
    • Neural population-level memory traces in the mouse hippocampus.

      Chen, Guifen; Wang, Lei Phillip; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology (2009-12-17)
      One of the fundamental goals in neurosciences is to elucidate the formation and retrieval of brain's associative memory traces in real-time. Here, we describe real-time neural ensemble transient dynamics in the mouse hippocampal CA1 region and demonstrate their relationships with behavioral performances during both learning and recall. We employed the classic trace fear conditioning paradigm involving a neutral tone followed by a mild foot-shock 20 seconds later. Our large-scale recording and decoding methods revealed that conditioned tone responses and tone-shock association patterns were not present in CA1 during the first pairing, but emerged quickly after multiple pairings. These encoding patterns showed increased immediate-replay, correlating tightly with increased immediate-freezing during learning. Moreover, during contextual recall, these patterns reappeared in tandem six-to-fourteen times per minute, again correlating tightly with behavioral recall. Upon traced tone recall, while various fear memories were retrieved, the shock traces exhibited a unique recall-peak around the 20-second trace interval, further signifying the memory of time for the expected shock. Therefore, our study has revealed various real-time associative memory traces during learning and recall in CA1, and demonstrates that real-time memory traces can be decoded on a moment-to-moment basis over any single trial.
    • NMDA Receptors Are Not Required for Pattern Completion During Associative Memory Recall

      Mei, Bing; Li, Fei; Gu, Yiran; Cui, Zhenzhong; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology (2011-04-29)
      Pattern completion, the ability to retrieve complete memories initiated by subsets of external cues, has been a major focus of many computation models. A previously study reports that such pattern completion requires NMDA receptors in the hippocampus. However, such a claim was derived from a non-inducible gene knockout experiment in which the NMDA receptors were absent throughout all stages of memory processes as well as animal's adult life. This raises the critical question regarding whether the previously described results were truly resulting from the requirement of the NMDA receptors in retrieval. Here, we have examined the role of the NMDA receptors in pattern completion via inducible knockout of NMDA receptors limited to the memory retrieval stage. By using two independent mouse lines, we found that inducible knockout mice, lacking NMDA receptor in either forebrain or hippocampus CA1 region at the time of memory retrieval, exhibited normal recall of associative spatial reference memory regardless of whether retrievals took place under full-cue or partial-cue conditions. Moreover, systemic antagonism of NMDA receptor during retention tests also had no effect on full-cue or partial-cue recall of spatial water maze memories. Thus, both genetic and pharmacological experiments collectively demonstrate that pattern completion during spatial associative memory recall does not require the NMDA receptor in the hippocampus or forebrain.
    • Predicting Impaired Extinction of Traumatic Memory and Elevated

      Nalloor, Rebecca Ipe; Bunting, Kristopher M.; Vazdarjanova, Almira; Brain & Behavior Discovery Institute; Department of Neurology (2011-05-18)
      Background: Emotionally traumatic experiences can lead to debilitating anxiety disorders,
    • Robust Action Recognition Using Multi-Scale Spatial-Temporal Concatenations of Local Features as Natural Action Structures

      Zhu, Xiaoyuan; Li, Meng; Li, Xiaojian; Yang, Zhiyong; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology; Department of Ophthalmology (2012-10-4)
      Human and many other animals can detect, recognize, and classify natural actions in a very short time. How this is achieved by the visual system and how to make machines understand natural actions have been the focus of neurobiological studies and computational modeling in the last several decades. A key issue is what spatial-temporal features should be encoded and what the characteristics of their occurrences are in natural actions. Current global encoding schemes depend heavily on segmenting while local encoding schemes lack descriptive power. Here, we propose natural action structures, i.e., multi-size, multi-scale, spatial-temporal concatenations of local features, as the basic features for representing natural actions. In this concept, any action is a spatial-temporal concatenation of a set of natural action structures, which convey a full range of information about natural actions. We took several steps to extract these structures. First, we sampled a large number of sequences of patches at multiple spatial-temporal scales. Second, we performed independent component analysis on the patch sequences and classified the independent components into clusters. Finally, we compiled a large set of natural action structures, with each corresponding to a unique combination of the clusters at the selected spatial-temporal scales. To classify human actions, we used a set of informative natural action structures as inputs to two widely used models. We found that the natural action structures obtained here achieved a significantly better recognition performance than low-level features and that the performance was better than or comparable to the best current models. We also found that the classification performance with natural action structures as features was slightly affected by changes of scale and artificially added noise. We concluded that the natural action structures proposed here can be used as the basic encoding units of actions and may hold the key to natural action understanding.
    • Statistics of eye movements in scene categorization and scene memorization

      Chen, Xin; Wan, Weibing; Yang, Zhiyong; Brain & Behavior Discovery Institute; Department of Ophthalmology; Vision Discovery Institute (2012-07-16)