Gabriel Lázaro-Muñoz

Sidman Instrumental Avoidance Initially Depends on Lateral and Basal Amygdala and Is Constrained by Central Amygdala-Mediated Pavlovian Processes

BACKGROUND The lateral (LA) and central (CE), but not basal (B), amygdala nuclei are necessary for reactive Pavlovian fear responses such as freezing. The amygdala also plays a key role in the acquisition and expression of active instrumental defensive behaviors, but little is known about the specific roles of amygdala nuclei. Using a Sidman active avoidance (AA) task, we examined the necessity of LA, B, and CE for learning and performance. Pavlovian freezing was simultaneously assessed to examine the contributions of amygdala nuclei to the transition from reactive to active defensive responding. METHODS Rats received electrolytic lesions of LA, CE, or B before AA training, or following overtraining. Rats that expressed low levels of AA performance during training received bilateral electrolytic lesions to CE to eliminate competing freezing reactions and rescue AA. AA performance and freezing were assessed. RESULTS Damage to LA and B, but not CE, impaired the acquisition of AA. Performance of AA became amygdala-independent following overtraining. CE lesions abolished Pavlovian freezing and rescued instrumental AA performance in rats that expressed low levels of avoidance responses and high levels of freezing during training. CONCLUSIONS Although the acquisition of Pavlovian fear depends on LA and CE, but not B, acquisition of instrumental AA is dependent on LA and B, but not CE. CE-dependent Pavlovian processes that control freezing can constrain avoidance behavior. Performance of well-trained AA becomes independent of all three amygdala nuclei. Thus, it appears that different output pathways of LA mediate reactive and active conditioned defensive responding.

Active vs. reactive threat responding is associated with differential c-Fos expression in specific regions of amygdala and prefrontal cortex

Active avoidance (AA) is an important paradigm for studying mechanisms of aversive instrumental learning, pathological anxiety, and active coping. Unfortunately, AA neurocircuits are poorly understood, partly because behavior is highly variable and reflects a competition between Pavlovian reactions and instrumental actions. Here we exploited the behavioral differences between good and poor avoiders to elucidate the AA neurocircuit. Rats received Sidman AA training and expression of the activity-dependent immediate-early gene c-fos was measured after a shock-free AA test. Six brain regions with known or putative roles in AA were evaluated: amygdala, periaqueductal gray, nucleus accumbens, dorsal striatum, prefrontal cortex (PFC), and hippocampus. Good avoiders showed little Pavlovian freezing and high AA rates at test, the opposite of poor avoiders. Although c-Fos activation was observed throughout the brain, differential activation was found only in subregions of amygdala and PFC. Interestingly, c-Fos correlated with avoidance and freezing in only five of 20 distinct areas evaluated: lateral amygdala, central amygdala, medial amygdala, basal amygdala, and infralimbic PFC. Thus, activity in specific amygdala-PFC circuits likely mediates the competition between instrumental actions and Pavlovian reactions after AA training. Individual differences in AA behavior, long considered a nuisance by researchers, may be the key to elucidating the AA neurocircuit and understanding pathological response profiles.

Endogenous GluR1-containing AMPA receptors translocate to asymmetric synapses in the lateral amygdala during the early phase of fear memory formation: an electron microscopic immunocytochemical study.

Although glutamate receptor 1 (GluR1)‐containing α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate receptors (GluR1‐AMPARs) are implicated in synaptic plasticity, it has yet to be demonstrated whether endogenous GluR1‐AMPARs undergo activity‐dependent trafficking in vivo to synapses to support short‐term memory (STM) formation. The paradigm of pavlovian fear conditioning (FC) can be used to address this question, because a discrete region—the lateral amygdala (LA)—has been shown unambiguously to be necessary for the formation of the associative memory between a neutral stimulus (tone [CS]) and a noxious stimulus (foot shock [US]). Acquisition of STM for FC can occur even in the presence of protein synthesis inhibitors, indicating that redistribution of pre‐existing molecules to synaptic junctions underlies STM. We employed electron microscopic immunocytochemistry to evaluate alterations in the distribution of endogenous AMPAR subunits at LA synapses during the STM phase of FC. Rats were sacrificed 40 minutes following three CS‐US pairings. In the LA of paired animals, relative to naïve animals, the proportion of GluR1‐AMPAR‐labeled synapses increased 99% at spines and 167% in shafts. In the LA of unpaired rats, for which the CS was never associated with the US, GluR1 immunoreactivity decreased 84% at excitatory shaft synapses. GluR2/3 immunoreactivity at excitatory synapses did not change detectably following paired or unpaired conditioning. Thus, the early phase of FC involves rapid redistribution specifically of the GluR1‐AMPARs to the postsynaptic membranes in the LA, together with the rapid translocation of GluR1‐AMPARs from remote sites into the spine head cytoplasm, yielding behavior changes that are specific to stimulus contingencies. J. Comp. Neurol. 518:4723–4739, 2010.

Looking for Trouble: Preventive Genomic Sequencing in the General Population and the Role of Patient Choice

Advances in genomics have led to calls for developing population-based preventive genomic sequencing (PGS) programs with the goal of identifying genetic health risks in adults without known risk factors. One critical issue for minimizing the harms and maximizing the benefits of PGS is determining the kind and degree of control individuals should have over the generation, use, and handling of their genomic information. In this article we examine whether PGS programs should offer individuals the opportunity to selectively opt out of the sequencing or analysis of specific genomic conditions (the menu approach) or whether PGS should be implemented using an all-or-nothing panel approach. We conclude that any responsible scale-up of PGS will require a menu approach that may seem impractical to some, but that draws its justification from a rich mix of normative, legal, and practical considerations.

Lesions of lateral or central amygdala abolish aversive Pavlovian-to-instrumental transfer in rats

Aversive Pavlovian conditioned stimuli (CSs) elicit defensive reactions (e.g., freezing) and motivate instrumental actions like active avoidance (AA). Pavlovian reactions require connections between the lateral (LA) and central (CeA) nuclei of the amygdala, whereas AA depends on LA and basal amygdala (BA). Thus, the neural circuits mediating conditioned reactions and motivation appear to diverge in the amygdala. However, AA is not ideal for studying conditioned motivation, because Pavlovian and instrumental learning are intermixed. Pavlovian-to-instrumental transfer (PIT) allows for the study of conditioned motivation in isolation. PIT refers to the ability of a Pavlovian CS to modulate a separately-trained instrumental action. The role of the amygdala in aversive PIT is unknown. We designed an aversive PIT procedure in rats and tested the effects of LA, BA, and CeA lesions. Rats received Pavlovian tone-shock pairings followed by Sidman shock-avoidance training. PIT was assessed by comparing shuttling rates in the presence and absence of the tone. Tone presentations facilitated instrumental responding. Aversive PIT was abolished by lesions of LA or CeA, but was unaffected by lesions of BA. These results suggest that LA and CeA are essential for aversive conditioned motivation. More specifically, the results are consistent with a model of amygdala processing in which the CS is encoded in the LA and then, via connections to CeA, the motivation to perform the aversive task is enhanced. These findings have implications for understanding the contribution of amygdala circuits to aversive instrumental motivation, but also for the relation of aversive and appetitive behavioral control.

Development of an aversive Pavlovian-to-instrumental transfer task in rat

Pavlovian-to-instrumental transfer (PIT) is an effect whereby a classically conditioned stimulus (CS) enhances ongoing instrumental responding. PIT has been extensively studied with appetitive conditioning but barely at all with aversive conditioning. Although its been argued that conditioned suppression is a form of aversive PIT, this effect is fundamentally different from appetitive PIT because the CS suppresses, instead of facilitates, responding. Five experiments investigated the importance of a variety of factors on aversive PIT in a rodent Sidman avoidance paradigm in which ongoing shuttling behavior (unsignaled active avoidance or USAA) was facilitated by an aversive CS. Experiment 1 demonstrated a basic PIT effect. Experiment 2 found that a moderate amount of USAA extinction produces the strongest PIT with shuttling rates best at around 2 responses per minute prior to the CS. Experiment 3 tested a protocol in which the USAA behavior was required to reach the 2-response per minute mark in order to trigger the CS presentation and found that this produced robust and reliable PIT. Experiment 4 found that the Pavlovian conditioning US intensity was not a major determinant of PIT strength. Experiment 5 demonstrated that if the CS and US were not explicitly paired during Pavlovian conditioning, PIT did not occur, showing that CS-US learning is required. Together, these studies demonstrate a robust, reliable and stable aversive PIT effect that is amenable to analysis of neural circuitry.

Improved ethical guidance for the return of results from psychiatric genomics research

There is an emerging consensus that genomic researchers should, at a minimum, offer to return to individual participants clinically valid, medically important and medically actionable genomic findings (for example, pathogenic variants in BRCA1) identified in the course of research. However, this is not a common practice in psychiatric genetics research. Furthermore, psychiatry researchers often generate findings that do not meet all of these criteria, yet there may be ethically compelling arguments to offer selected results. Here, we review the return of results debate in genomics research and propose that, as for genomic studies of other medical conditions, psychiatric genomics researchers should offer findings that meet the minimum criteria stated above. Additionally, if resources allow, psychiatry researchers could consider offering to return pre-specified ‘clinically valuable’ findings even if not medically actionable—for instance, findings that help corroborate a psychiatric diagnosis, and findings that indicate important health risks. Similarly, we propose offering ‘likely clinically valuable’ findings, specifically, variants of uncertain significance potentially related to a participant’s symptoms. The goal of this Perspective is to initiate a discussion that can help identify optimal ways of managing the return of results from psychiatric genomics research.

Genomic Contraindications for Heart Transplantation

An ethical analysis of a case in which genomic findings led physicians to reconsider a patient’s eligibility for cardiac transplantation. Genome sequencing raises new ethical challenges. Decoding the genome produces new forms of diagnostic and prognostic information; however, the information is often difficult to interpret. The connection between most genetic variants and their phenotypic manifestations is not understood. This scenario is particularly true for disorders that are not associated with an autosomal genetic variant. The analytic uncertainty is compounded by moral uncertainty about how, exactly, the results of genomic testing should influence clinical decisions. In this Ethics Rounds, we present a case in which genomic findings seemed to play a role in deciding whether a patient was to be listed as a transplant candidate. We then asked experts in bioethics and cardiology to discuss the implications of such decisions.

Responsible Translation of Psychiatric Genetics and Other Neuroscience Developments: In Need of Empirical Bioethics Research

Responsible Translation of Psychiatric Genetics and Other Neuroscience Developments: In Need of Empirical Bioethics Research Gabriel Lázaro-Muñoz To cite this article: Gabriel Lázaro-Muñoz (2017) Responsible Translation of Psychiatric Genetics and Other Neuroscience Developments: In Need of Empirical Bioethics Research, The American Journal of Bioethics, 17:4, 33-35, DOI: 10.1080/15265161.2017.1284917 To link to this article: http://dx.doi.org/10.1080/15265161.2017.1284917

Manipulating Human Memory Through Reconsolidation: Stones Left Unturned

Memory reconsolidation is the process by which a previously stored memory, when recalled, becomes unstable and susceptible to modification before being re-stored. Reconsolidation disruption protocols (RDPs) may prove to be powerful therapeutic tools for psychiatric disorders that involve maladaptive learning and memory. However, Elsey and Kindt (2016) present an overly optimistic and incomplete portrayal of the state of reconsolidation research, which leads them to minimize scientific and ethical apprehensions about manipulating human memory through reconsolidation. This is problematic because their depiction of reconsolidation research could mislead stakeholders—such as clinicians, patients, and health policymakers—when evaluating the potential harms and benefits of translating RDPs to the clinical context. We address three pressing concerns about the authors’ depiction of reconsolidation research: (1) insufficient and contradictory evidence about the effectiveness or clinical utility of propranolol RDPs; (2) risk for extemporaneous translation of propranolol RDP research to clinical practice; and (3) lack of discussion of other kinds of RDPs that generate significant ethical challenges—it is necessary to consider different kinds of RDPs when drawing conclusions about the ethics of a topic as broad as “manipulating human memory through reconsolidation.”