Increasing the validity of experimental models for depression

Major depressive disorder (MDD) is a central nervous system disorder characterized by the culmination of profound disturbances in mood and affective regulation. Animal models serve as a powerful tool for investigating the neurobiological mechanisms underlying this disorder; however, little standardization exists across the wide range of available modeling approaches most often employed. This review will illustrate some of the most challenging obstacles faced by investigators attempting to associate depressive-like behaviors in rodents with symptoms expressed in MDD. Furthermore, a novel series of depressive-like criteria based on correlating behavioral endophenotypes, novel in vivo neurophysiological measurements, and molecular/cellular analyses within multiple brain are proposed as a potential solution to overcoming this barrier. Ultimately, linking the neurophysiological and cellular/biochemical actions that contribute to the expression of a defined MDD-like syndrome will dramatically extend the translational value of the most valid animal models of MDD.     

Extinction models and conservation

In their seminal book, The Theory of Island Biogeography, MacArthur and Wilson (1) proposed that '(the principles derived from island biogeography] apply, and will apply to an accelerating extent in the future, to formerly continuous natural habitats now being broken up by the encroachment of civilization'. Debate over the validity of this statement has raged for a decade, focusing particularly on reserve design 'rules' and whether a single large reserve or several small reserves will protect more species? These arguments have led to some new insights, if not a fresh perspective, on some old but fundamental topics in ecology and evolution. Most notable among these is extinction.     

Neuronal signalling of fear memory

The learning and remembering of fearful events depends on the integrity of the amygdala, but how are fear memories represented in the activity of amygdala neurons? Here, we review recent electrophysiological studies indicating that neurons in the lateral amygdala encode aversive memories during the acquisition and extinction of Pavlovian fear conditioning. Studies that combine unit recording with brain lesions and pharmacological inactivation provide evidence that the lateral amygdala is a crucial locus of fear memory. Extinction of fear memory reduces associative plasticity in the lateral amygdala and involves the hippocampus and prefrontal cortex. Understanding the signalling of aversive memory by amygdala neurons opens new avenues for research into the neural systems that support fear behaviour.     

Extinction thresholds in deterministic and stochastic epidemic models

The basic reproduction number, ?(0), one of the most well-known thresholds in deterministic epidemic theory, predicts a disease outbreak if ?(0)>1. In stochastic epidemic theory, there are also thresholds that predict a major outbreak. In the case of a single infectious group, if ?(0)>1 and i infectious individuals are introduced into a susceptible population, then the probability of a major outbreak is approximately 1-(1/?(0))( i ). With multiple infectious groups from which the disease could emerge, this result no longer holds. Stochastic thresholds for multiple groups depend on the number of individuals within each group, i ( j ), j=1, …, n, and on the probability of disease extinction for each group, q ( j ). It follows from multitype branching processes that the probability of a major outbreak is approximately [Formula: see text]. In this investigation, we summarize some of the deterministic and stochastic threshold theory, illustrate how to calculate the stochastic thresholds, and derive some new relationships between the deterministic and stochastic thresholds.     

恐惧记忆消散的神经生物学机制研究进展

恐惧消散被认为是一种通过形成新的抑制性学习来拮抗最初的恐惧记忆的复杂过程。目前,通过旨在促进恐惧消散的疗法治疗诸如焦虑症等神经精神疾病已在临床上取得了较好的疗效,因此,如何更有效持久地维持恐惧消散记忆具有重要的意义。围绕与恐惧记忆消散相关的脑区及恐惧记忆消散的分子机制进行阐述,有助于更深入地理解恐惧记忆消散相关的神经生物学机制,为后续研究提供新的方向。     

Molecular mechanisms of fear learning and memory

Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias.     

Extinction antagonizes olfactory memory at the subcellular level

Memory loss occurs by diverse mechanisms, as different time constants of performance decrement and sensitivities to experimental manipulations suggest. While the phenomena of memory decay, interference, and extinction are well established behaviorally, little is known about them at the circuit or molecular level. In Drosophila, odorant memories lasting up to 3 hr can be localized to mushroom body Kenyon cells, a single neuronal level in the olfactory pathway. The plasticity underlying this memory trace can be induced without Kenyon cell synaptic output. Experimental extinction, i.e., presentation of the conditioned stimulus without the reinforcer, reduces memory performance and does so at the same circuit level as memory formation. Thus, unreinforced presentation of learned odorants antagonizes intracellularly the signaling cascade underlying memory formation.     

Extinction models for cancer stem cell therapy

Cells with stem cell-like properties are now viewed as initiating and sustaining many cancers. This suggests that cancer can be cured by driving these cancer stem cells to extinction. The problem with this strategy is that ordinary stem cells are apt to be killed in the process. This paper sets bounds on the killing differential (difference between death rates of cancer stem cells and normal stem cells) that must exist for the survival of an adequate number of normal stem cells. Our main tools are birth-death Markov chains in continuous time. In this framework, we investigate the extinction times of cancer stem cells and normal stem cells. Application of extreme value theory from mathematical statistics yields an accurate asymptotic distribution and corresponding moments for both extinction times. We compare these distributions for the two cell populations as a function of the killing rates. Perhaps a more telling comparison involves the number of normal stem cells N_H at the extinction time of the cancer stem cells. Conditioning on the asymptotic time to extinction of the cancer stem cells allows us to calculate the asymptotic mean and variance of N_H. The full distribution of N_H can be retrieved by the finite Fourier transform and, in some parameter regimes, by an eigenfunction expansion. Finally, we discuss the impact of quiescence (the resting state) on stem cell dynamics. Quiescence can act as a sanctuary for cancer stem cells and imperils the proposed therapy. We approach the complication of quiescence via multitype branching process models and stochastic simulation. Improvements to the τ-leaping method of stochastic simulation make it a versatile tool in this context. We conclude that the proposed therapy must target quiescent cancer stem cells as well as actively dividing cancer stem cells. The current cancer models demonstrate the virtue of attacking the same quantitative questions from a variety of modeling, mathematical, and computational perspectives.     

杏仁复合体β受体参与条件性恐惧记忆

杏仁复合体是条件性恐惧记忆形成和储存的关键脑区。杏仁复合体β受体参与条件性恐惧记忆的巩固。β受体激活易化杏仁复合体内突触传递的长时程增强,增强条件性恐惧记忆的巩固;而阻断β受体则抑制杏仁复合体内突触传递的长时程增强,损害条件性恐惧记忆的巩固。     

Reversible plasticity of fear memory-encoding amygdala synaptic circuits even after fear memory consolidation

It is generally believed that after memory consolidation, memory-encoding synaptic circuits are persistently modified and become less plastic. This, however, may hinder the remaining capacity of information storage in a given neural circuit. Here we consider the hypothesis that memory-encoding synaptic circuits still retain reversible plasticity even after memory consolidation. To test this, we employed a protocol of auditory fear conditioning which recruited the vast majority of the thalamic input synaptic circuit to the lateral amygdala (T-LA synaptic circuit; a storage site for fear memory) with fear conditioning-induced synaptic plasticity. Subsequently the fear memory-encoding synaptic circuits were challenged with fear extinction and re-conditioning to determine whether these circuits exhibit reversible plasticity. We found that fear memory-encoding T-LA synaptic circuit exhibited dynamic efficacy changes in tight correlation with fear memory strength even after fear memory consolidation. Initial conditioning or re-conditioning brought T-LA synaptic circuit near the ceiling of their modification range (occluding LTP and enhancing depotentiation in brain slices prepared from conditioned or re-conditioned rats), while extinction reversed this change (reinstating LTP and occluding depotentiation in brain slices prepared from extinguished rats). Consistently, fear conditioning-induced synaptic potentiation at T-LA synapses was functionally reversed by extinction and reinstated by subsequent re-conditioning. These results suggest reversible plasticity of fear memory-encoding circuits even after fear memory consolidation. This reversible plasticity of memory-encoding synapses may be involved in updating the contents of original memory even after memory consolidation.     

Hippocampal-amygdala memory circuits govern experience-dependent observational fear

1. Download : Download high-res image (178KB)
2. Download : Download full-size image

     

Extinction of populations by inbreeding depression under stochastic environments

Inbreeding depression may induce rapid extinction due to positive feedbacks between inbreeding depression and reduction of population size, which is often referred to as extinction vortex by inbreeding depression. The present analysis has demonstrated that the extinction vortex is likely to happen with realistic parameter values of genomic mutation rate of lethals or semilethals, equilibrium population size, intrinsic rate of natural increase, and rate of population decline caused by nongenetic extrinsic factors. Simulation models incorporating stochastic fluctuations of population size further indicated that extinction by inbreeding depression is facilitated by environmental fluctuations in population size. The results suggest that there is a positive interaction between genetic stochasticity and environmental stochasticity for extinction of populations by inbreeding depression. Received: May 10, 1999 / Accepted: November 5, 1999     

Antidepressant activity of standardized extract of Bacopa monniera in experimental models of depression in rats.

Bacopa monniera Wettst. (syn. Herpestis monniera L.; Scrophulariaceae) is a commonly used Ayurvedic drug for mental disorders. The standardized extract was reported earlier to have significant anti-oxidant effect, anxiolytic activity and improve memory retention in Alzheimer's disease. Presently, the standardized methanolic extract of Bacopa monniera (bacoside A - 38.0+/-0.9) was investigated for potential antidepressant activity in rodent models of depression. The effect was compared with the standard antidepressant drug imipramine (15 mg/kg, ip). The extract when given in the dose of 20 and 40 mg/kg, orally once daily for 5 days was found to have significant antidepressant activity in forced swim and learned helplessness models of depression and was comparable to that of imipramine.     

Mineralocorticoid receptors in control of emotional arousal and fear memory

The stress hormone corticosterone acts via two receptor types in the brain: the mineralocorticoid (MR) and the glucocorticoid receptor (GR). Both receptors are involved in processing of stressful events. A disbalance of MR:GR functions is thought to promote stress-related disorders. Here we studied the effect of stress on emotional and cognitive behaviors in mice with forebrain-specific inactivation of the MR gene (MR^CaMKCre, 4 months old; and control littermates). MR^CaMKCre mice responded to prior stress (5 min of restraint) with higher arousal and less locomotor activity in an exploration task. A fear conditioning paradigm allowed assessing in one experimental procedure both context- and cue-related fear. During conditioning, MR^CaMKCre mice expressed more cue-related freezing. During memory test, contextual freezing remained potentiated, while control mice distinguished between cue (more freezing) and context episodes (less freezing) in the second memory test. At this time, plasma corticosterone levels of MR^CaMKCre mice were 40% higher than in controls. We conclude that control of emotional arousal and adaptive behaviors is lost in the absence of forebrain MR, and thus, anxiety-related responses are and remain augmented. We propose that such a disbalance in MR:GR functions in MR^CaMKCre mice provides the conditions for an animal model for anxiety-related disorders.     

Synaptic correlates of associative fear memory in the lateral amygdala

1. Download : Download high-res image (188KB)
2. Download : Download full-size image

     

Extinction of populations due to inbreeding depression with demographic disturbances

The process of population extinction due to inbreeding depression with constant demographic disturbances every generation is analysed using a population genetic and demographic model. The demographic disturbances introduced into the model represent loss of population size that is induced by any kind of human activities, e.g. through hunting and destruction of habitats. The genetic heterozygosity among recessive deleterious genes and the population size are assumed to be in equilibrium before the demographic disturbances start. The effects of deleterious mutations are represented by decreases in the growth rate and carrying capacity of a population. Numerical simulations indicate rapid extinction due to synergistic interaction between inbreeding depression and declining population size for realistic ranges of per-locus mutation rate, equilibrium population size, intrinsic rate of population growth, and strength of demographic disturbances. Large populations at equilibrium are more liable to extinction when disturbed due to inbreeding depression than small populations. This is a consequence of the fact that large populations maintain more recessive deleterious mutations than small populations. The rapid extinction predicted in the present study indicates the importance of the demographic history of a population in relation to extinction due to inbreeding depression.     

Effect of beta-lactotensin on acute stress and fear memory

β-Lactotensin (β-LT) is a bioactive peptide derived from bovine milk β-lactoglobulin and is a natural ligand for neurotensin receptors. We examined the effect of β-LT on restraint stress and fear memory in mice. Mice subjected to acute restraint stress exhibited a decreased number of head-dips and increased head-dip latency compared to non-stressed controls in the hole-board test, reflecting increased stress-induced behaviors. However, prior administration of β-LT improved the behaviors caused by stress. The anti-stress effect of β-LT was blocked by levocabastine, a neurotensin receptor subtype 2 (NTR2) antagonist. In the fear-conditioning test, the duration of freezing responses by cued fear conditioning was significantly reduced in mice administered β-LT compared with control mice. These results suggest that β-LT has an anti-stress effect and promotes the extinction of fear memory, which may be mediated by NTR2.