Min Whan Jung

Neural circuits and mechanisms involved in Pavlovian fear conditioning: A critical review

Pavlovian or classical fear conditioning is recognized as a model system to investigate the neurobiological mechanisms of learning and memory in the mammalian brain and to understand the root of fear-related disorders in humans. In recent decades, important progress has been made in delineating the essential neural circuitry and cellular-molecular mechanisms of fear conditioning. Converging lines of evidence indicate that the amygdala is necessarily involved in the acquisition, storage and expression of conditioned fear memory, and long-term potentiation (LTP) in the lateral nucleus of the amygdala is often proposed as the underlying synaptic mechanism of associative fear memory. Recent studies further implicate the prefrontal cortex-amygdala interaction in the extinction (or inhibition) of conditioned fear. Despite these advances, there are unresolved issues and findings that challenge the validity and sufficiency of the current amygdalar LTP hypothesis of fear conditioning. The purpose of this review is to critically evaluate the strengths and weaknesses of evidence indicating that fear conditioning depend crucially upon the amygdalar circuit and plasticity.

Distinct Roles of Rodent Orbitofrontal and Medial Prefrontal Cortex in Decision Making

We investigated how different subregions of rodent prefrontal cortex contribute to value-based decision making, by comparing neural signals related to animals choice, its outcome, and action value in orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) of rats performing a dynamic two-armed bandit task. Neural signals for upcoming action selection arose in the mPFC, including the anterior cingulate cortex, only immediately before the behavioral manifestation of animals choice, suggesting that rodent prefrontal cortex is not involved in advanced action planning. Both OFC and mPFC conveyed signals related to the animals past choices and their outcomes over multiple trials, but neural signals for chosen value and reward prediction error were more prevalent in the OFC. Our results suggest that rodent OFC and mPFC serve distinct roles in value-based decision making and that the OFC plays a prominent role in updating the values of outcomes expected from chosen actions.

Neural Basis of Reinforcement Learning and Decision Making

Reinforcement learning is an adaptive process in which an animal utilizes its previous experience to improve the outcomes of future choices. Computational theories of reinforcement learning play a central role in the newly emerging areas of neuroeconomics and decision neuroscience. In this framework, actions are chosen according to their value functions, which describe how much future reward is expected from each action. Value functions can be adjusted not only through reward and penalty, but also by the animals knowledge of its current environment. Studies have revealed that a large proportion of the brain is involved in representing and updating value functions and using them to choose an action. However, how the nature of a behavioral task affects the neural mechanisms of reinforcement learning remains incompletely understood. Future studies should uncover the principles by which different computational elements of reinforcement learning are dynamically coordinated across the entire brain.

Role of Striatum in Updating Values of Chosen Actions

The striatum is thought to play a crucial role in value-based decision making. Although a large body of evidence suggests its involvement in action selection as well as action evaluation, underlying neural processes for these functions of the striatum are largely unknown. To obtain insights on this matter, we simultaneously recorded neuronal activity in the dorsal and ventral striatum of rats performing a dynamic two-armed bandit task, and examined temporal profiles of neural signals related to animals choice, its outcome, and action value. Whereas significant neural signals for action value were found in both structures before animals choice of action, signals related to the upcoming choice were relatively weak and began to emerge only in the dorsal striatum ∼200 ms before the behavioral manifestation of the animals choice. In contrast, once the animal revealed its choice, signals related to choice and its value increased steeply and persisted until the outcome of animals choice was revealed, so that some neurons in both structures concurrently conveyed signals related to animals choice, its outcome, and the value of chosen action. Thus, all the components necessary for updating values of chosen actions were available in the striatum. These results suggest that the striatum not only represents values associated with potential choices before animals choice of action, but might also update the value of chosen action once its outcome is revealed. In contrast, action selection might take place elsewhere or in the dorsal striatum only immediately before its behavioral manifestation.

Ginsenoside Rb1 and Rg1 Improve Spatial Learning and Increase Hippocampal Synaptophysin Level in Mice

We investigated the cognition enhancing effects of ginsenoside Rb1 and Rg1. Mice were trained in a Morris water maze following injection (i.p.) of Rb1 (1 mg/kg) or Rg1 (1 mg/kg) for 4 days. Both Rb1‐ and Rg1‐injected mice showed enhanced spatial learning compared to control animals. The hippocampus, but not the frontal cortex, of treated mice contained higher density of a synaptic marker protein, synaptophysin, compared to control mice. Electrophysiological recordings in hippocampal slices revealed that Rb1 or Rg1 injection did not change the magnitude of paired‐pulse facilitation or long‐term potentiation. Our results suggest that Rb1 and Rg1 enhance spatial learning ability by increasing hippocampal synaptic density without changing plasticity of individual synapses. J. Neurosci. Res. 63:509–515, 2001.

Lovastatin enhances Aβ production and senile plaque deposition in female Tg2576 mice

A recent clinical study showed that statins, which are inhibitors of cholesterol biosynthesis pathway, reduced the prevalence of Alzheimers disease (AD). Animal studies that have employed high cholesterol diet indicate significant relationship between cholesterol level and senile plaque deposition. Here, we investigated the effects of lovastatin on beta-amyloid production and senile plaque deposition in an animal model of AD (Tg2576 mice). As expected, lovastatin treatment reduced plasma cholesterol level in both male and female mice. However, lovastatin enhanced the amounts of beta-amyloid and other beta-secretase derived peptides in females, but not in males. Likewise, lovastatin increased the number of plaques in the hippocampus and cortex of females, but not in males. Lovastatin did not change the amounts of full-length or alpha-secretase processed amyloid precursor protein (APP), or presenilin 1 (PS1) in either sex. Thus, lovastatin lowers cholesterol level in both genders, but enhances beta-amyloid production and senile plaque deposition only in brains of female Tg2576 mice. Our results suggest that low plasma cholesterol levels might be a risk factor for AD in females.

Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity.

Asiaticoside (AS) derivatives were tested for potential protective effects against Aβ‐induced cell death. Of the 28 AS derivatives tested, asiatic acid (AA), asiaticoside 6 (AS6), and SM2 showed strong inhibition of Aβ‐induced death of B103 cells at 1 μM. The three AS derivatives were further tested for their effects on free radical injury and apoptosis. All three AS derivatives reduced H2O2‐induced cell death and lowered intracellular free radical concentration, but AA showed the strongest protection. In contrast, SM2 was the most effective blocker of staurosporine‐induced apoptosis. These results suggest that the three AS derivatives block Aβ toxicity by acting through different cellular mechanisms. When applied to hippocampal slices, AA, SM2, and AS6 did not alter n‐methyl‐D‐aspartic acid (NMDA) or non‐NMDA receptor‐mediated synaptic transmission, paired‐pulse facilitation or induction of long‐term potentiation in the field CA1. These results indicate that the three AS derivatives do not alter physiological properties of the hippocampus at the concentration that blocks Aβ‐induced cell death. Therefore AS6, AA, and SM2 can be regarded as reasonable candidates for a therapeutic Alzheimers disease drug that protects neurons from Aβ toxicity. J. Neurosci. Res. 58:417–425, 1999.

Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus

The dentate gyrus (DG) is among the few areas in the mammalian brain where production of new neurons continues in the adulthood. Although its functional significance is not completely understood, several lines of evidence suggest the role of DG neurogenesis in learning and memory. Considering that long-term potentiation (LTP) is a prime candidate for the process underlying hippocampal learning and memory, these results raise the possibility that LTP and neurogenesis are closely related. Here, we investigated whether or not LTP induction in the afferent pathway triggers enhanced proliferation of progenitor cells in the DG. LTP was induced by tetanic stimulation in perforant path-DG synapses in one hemisphere, and the number of newly generated progenitor (BrdU-labeled) cells in the DG was quantified. Compared with the control hemisphere (stimulated with low-frequency pulses), the LTP-induced hemisphere contained a significantly higher number of newly generated progenitor cells in the dorsal as well as ventral DG. When CPP, an NMDA receptor antagonist, was administered, tetanic stimulation neither induced LTP nor enhanced progenitor cell proliferation, indicating that NMDA receptor activation, rather than tetanic stimulation per se, is responsible for enhanced progenitor proliferation in the control animal. Our results show that tetanic stimulation of perforant path sufficient to induce LTP increases progenitor proliferation in adult DG in an NMDA receptor-dependent manner.

ERK1/2 is an endogenous negative regulator of the gamma-secretase activity.

As an essential protease in the generation of amyloid β, γ‐secretase is believed to play an important role in the pathogenesis of Alzheimers disease. Although a great deal of progress has been made in identifying the components of γ‐secretase complex, the endogenous regulatory mechanism of γ‐secretase is unknown. Here we show that γ‐secretase is endogenously regulated via extracellular signal regulated MAP kinase (ERK) 1/2‐dependent mitogen‐activated protein kinase (MAPK) pathway. The inhibition of ERK1/2 activity, either by a treatment with a MEK inhibitor or an ERK knockdown transfection, dramatically increased γ‐secretase activity in several different cell types. JNK or p38 kinase inhibitors had little effect, indicating that the effect is specific to ERK1/2‐dependent MAPK pathway. Conversely, increased ERK1/2 activity, by adding purified active ERK1/2 or EGF‐induced activation of ERK1/2, significantly reduced γsecretase activity, demonstrating down‐regulation of γ‐secretase activity by ERK1/2. Whereas γsecretase expression was not affected by ERK1/2, its activity was enhanced by phosphatase treatment, indicating that ERK1/2 regulates γ‐secretase activity by altering the pattern of phophorylation. Among the components of isolated γ‐secretase complex, only nicastrin was phosphorylated by ERK1/2, and it precipitated with ERK1/2 in a co‐immunoprecipitation assay, which suggests binding between ERK1/2 and nicastrin. Our results show that ERK1/2 is an endogenous regulator of γ‐secretase, which raises the possibility that ERK1/2 down‐regulates γsecretase activity by directly phosphorylating nicastrin.

Neuroprotective effects of estrogen against beta-amyloid toxicity are mediated by estrogen receptors in cultured neuronal cells

Although estrogen is known to exert beneficial effects on Alzheimers disease, its underlying cellular mechanisms have not been clear. In this study we investigated whether or not neuroprotective effects of estrogen are mediated by estrogen receptors (ERs). Treatment of estrogen (1.8 nM) reduced beta-amyloid (Abeta)-induced death of ER-expressing W4 cells. This effect of estrogen was blocked by a specific ER blocker ICI 182,780. When estrogen was treated to HT22 cells, which lack functional ERs, Abeta-induced cell death was not affected. Transfection of HT22 cells with human ERalpha, but not ERbeta, restored protective action of estrogen against Abeta. Hoechst staining revealed that estrogen protected ERalpha-expressing cells by blocking Abeta-induced apoptosis. These results indicate that estrogen blocks Abeta-induced cell death via ERalpha-dependent pathways.