• 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.
    • 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.
    • 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.
    • 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.