PIONEER IN BEHAVIORAL PHARMACOLOGY: A TRIBUTE TO JOSEPH V. BRADY

The contributions of Joseph V. Brady to behavioral pharmacology span more than 50 years and range from early studies using the Estes-Skinner (conditioned emotional response) procedure to examine drug effects and various physiological processes in experimental animals to the implementation of mobile methadone treatment services and to small group behavioral analyses in simulated space environments. This expansive range of activities is based on Brady's insight and innovative use of behavioral procedures, his spirited and unabashed enthusiasm for the discipline and its philosophical underpinnings, together with a collegiality and commitment to the experimental analysis of behavior that is both legendary and inspirational. These contributions are summarized and highlighted in this tribute that focuses primarily on Brady's contributions to behavioral pharmacology but which also acknowledges his conceptual and technical contributions spanning multiple disciplines.     

Fetal Programming: Prenatal Origins of Health and Illness

ABSTRACT— Research on young animals and humans has demonstrated the critical importance of the fetal stage as a formative period in normal development. However, the significance of these findings has not always been incorporated into our thinking when trying to elucidate the origins of health and disease. It is not only that babies react to the state of the mother and to salient environmental events while still in the uterus. This stimulation and priming seems to be essential for guiding the optimal maturation of the nervous, endocrine, and immune systems. Experiences during prenatal life also program the regulatory set points that will govern physiology in adulthood. During this malleable maturational phase, these biological processes should be viewed as flexible "learning systems" that guide the developmental trajectory toward health or derail it toward pathology. Our studies on infant primates have shown that the competence of their immune responses and the structure and activity of certain brain regions, as well as many aspects of behavior and emotional reactivity, are strongly affected by the pregnancy conditions of their mothers.     

论肿瘤免疫的复杂性

免疫系统是一个复杂自适应巨系统,它还具有开放复杂巨系统的所有特征。体内已建立的肿瘤是一个复杂适应系统,两者间的相互作用造就了肿瘤免疫的复杂性。本文从复杂性科学角度阐释肿瘤免疫,以期对肿瘤细胞免疫治疗的研究有所裨益。     

Hippocampal low-frequency stimulation and chronic mild stress similarly disrupt fear extinction memory in rats

Disruptions of fear extinction-related potentiation of synaptic efficacy in the connection between the hippocampus (HPC) and the medial prefrontal cortex (mPFC) have been shown to impair the recall of extinction memory. This study was undertaken to examine if chronic mild stress (CMS), which is known to alter induction of HPC–mPFC long-term potentiation, would also interfere with both extinction-related HPC–mPFC potentiation and extinction memory. Following fear conditioning (5 tone-shock pairings), rats were submitted to fear extinction (20 tone-alone presentations), which produced an increase in the amplitude of HPC–mPFC field potentials. HPC low-frequency stimulation (LFS), applied immediately after training, suppressed these changes and induced fear return during the retention test (5 tone-alone presentations). CMS, delivered before fear conditioning, did not interfere with fear extinction but blocked the development of extinction-related potentiation in the HPC–mPFC pathway and impaired the recall of extinction. These findings suggest that HPC LFS may provoke metaplastic changes in HPC outputs that may mimic alterations associated with a history of chronic stress.     

二级强化程序在药物成瘾研究中的应用

二级强化程序是一种以物质的强化效应为基础,评价药物的精神依赖性潜力的方法,将其应用到自身给药实验中,即为二级强化自身给药模型。在这个模型中,动物在条件性刺激的影响下按压杠杆以寻求药物的行为反映了其对成瘾性药物的渴求。使用二级强化程序,人们发现：条件性刺激既能够影响觅药行为的获得和保持,也能够影响这种行为的消退;伏隔核的核区、杏仁核基底外侧部和内侧前额皮层等部位在药物相关的条件性刺激诱导动物产生觅药行为的过程中起重要作用。二级强化程序的应用为开发治疗药物成瘾的物质提供了一条新思路     

心理神经免疫学研究

心理神经免疫学（Psychoneuroimmunology）是一门探索人类心身健康奥秘的新型边缘学科。它研究神经系统如何将心理因素转换为可以影响健康的生理状态的机制,特别是脑和行为如何影响免疫系统,又如何受到免疫系统的影响的。免疫系统和神经系统之间是否真正存在联系一直有争论,我们实验室围绕高级神经活动对免疫系统的作用开展了研究。工作包括：条件反射性免疫抑制和增强、情绪应激与免疫、心理行为干预与癌症等。这些工作不仅证实了心理调控,比如信号刺激、情绪和意念想象等,确实可以影响免疫系统的功能,而且对有关机制进行了探讨     

干预条件性恐惧记忆表达的相关影响因素分析

创伤后应激障碍是个体经历严重应激后形成的一种焦虑障碍, 对其治疗的关键是熄灭由创伤应激导致的条件性恐惧记忆。条件性恐惧的动物模型研究发现恐惧记忆一旦获得后就难以熄灭, 容易复发, 而这一点也是PTSD的关键临床症状表现之一。因此, 如何更好更持久地熄灭恐惧记忆, 是一个具有重要理论和临床意义的研究热点。本文围绕促进恐惧记忆的长久消退和破坏恐惧记忆的再巩固两方面的行为或药理干预及机制进行综述。针对本文所述的几种基础实验处理, 临床上可以研究治疗创伤后应激障碍的相应疗法。     

The effect of on‐ or off‐line extinction of a first‐order conditioned stimulus on a second‐order conditioned response in rats

In a water‐licking experiment with rats, the effects of the extinction of a first‐order conditioned stimulus (CS1) on the suppression of licking established for a second‐order conditioned stimulus (CS2) were explored. Extinction of the first‐order conditioned response (CR1) attenuated the conditioned suppression induced by CS2 when the rats had been allowed to lick water during the CR1 extinction phase. However, if water had been unavailable during the CR1 extinction phase, suppression by CS2 was not affected. The latter result is consistent with other studies of rats' conditioned suppression and suggests that the underlying mechanism of second‐order conditioning in this experiment is a connection between CS2 and the response elicited by CS1 rather than a CS2‐CS1 connection. The former result was interpreted as the CR1 extinction phase encouraging the rats to lick water despite the fear elicited by CS1, and thus, in testing, they licked despite the fear elicited by CS2.     

条件性恐惧记忆提取消退干预范式

提取消退(retrieval-extinction, Ret+Ext)范式是基于记忆再巩固理论, 利用消退训练(extinction, Ext)能改变条件刺激(conditioned stimulus, CS)的恐惧效价特点, 把消退训练应用到再巩固时间窗内来改写(rewrite)恐惧记忆, 消除恐惧反应。提取消退范式是对传统暴露疗法和药物治疗的创新和拓展, 不仅为创伤性记忆的治疗提供一种非侵入性的技术, 而且也为改写人类记忆、积极心理学探索人类幸福感方面开辟了一种全新的理论视角。     

女性生理周期对条件性恐惧习得和消退的影响

动物研究显示, 雌激素调节条件性恐惧习得和消退, 但是, 人类的性激素对条件性恐惧习得和消退的影响还不太清楚。因此, 本研究以大学生为研究对象, 考察女性不同生理周期对条件性情境恐惧的习得和消退的影响。20名经前期和20名经期女被试暴露于3种情境下：无厌恶刺激情境(N)、可预测情境(P)和不可预测情境(U), 预测此3种情境下是否出现厌恶刺激。以在线索条件下和无线索条件下对厌恶刺激的主观预期值为因变量。研究结果显示:在习得阶段, 经期女性在P情境下的条件性线索恐惧的主观预期值高于经前期女性; 经前期女性在3种情境下的条件性情境恐惧的主观预期值都高于经期女性, 但只在N情境和P情境, 与经期女性相比, 经前期女性对厌恶刺激的主观预期值存在显著差异。在消退阶段, 与经期女性相比, 经前期女性在3种情境下的条件性情境恐惧的主观预期值更高, 且经前期女性对厌恶刺激的主观预期值在N情境和P情境显著高于经期女性。该结果显示, 经前期女性对条件性情境恐惧易习得难消退, 表明此生理阶段的性激素影响大脑的情绪调节功能, 从而影响条件性情境恐惧。