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Selection of procedures and protocols affect scientific outcomes
Posted by 08 Jul 2013 at 23:22 GMTon
Individual differences in temperament, cognition and behavior in non-human and human primates likely depend upon extraordinarily similar patterns of variation in molecular genetic and neuro-anatomical, -physiological and –chemical mechanisms. For that reason, studies of these phenotypes in monkeys can advance our understanding of the biological bases of human behavior – both normal and abnormal. If these parallels hold, it stands to reason that some monkeys would exhibit atypical behaviors reminiscent of human psychopathology and be useful model systems for investigating the underlying neurobiology. There are a number of efforts underway to examine the genetic and neural basis of typical and atypical behaviors in colony-reared monkeys, with this very goal in mind.
This article surveyed behavior in a group of male macaques that had experienced an anomalous sociodevelopmental history and potentially distressing procedures that could affect the outcome measures. Chief amongst these appears to be the collection of biological materials, including blood (by venipuncture) and cerebrospinal fluid (by lumbar puncture), in monkeys with no sedation, anesthesia or pain relief. In this study, monkeys were physically restrained during both protocols. Both are painful procedures, with lumbar puncture representing a particular risk to both the researcher collecting the sample and, importantly, to the animal. Lumbar puncture in human subjects – which many individuals report as very painful - is sometimes conducted in ambulatory settings with no sedation or anesthesia, but local pain block is typically used. Moreover, headaches, often intense in severity, are a common post-tap symptom. For these reasons, as well as to avoid the distress of physical restraint and the risk to the subject associated with a sudden movement while the needle is in place, chemical sedation or anesthesia are the standard of care in virtually every veterinary setting in the US, Canada and Europe (as well as many others). It is surprising that the potential risk to the subjects and the likely distress caused by these procedures (and the impact of this distress on the behavior of the subjects) appears not to have triggered a deeper look at whether sedation, anesthesia and/or analgesia should have been used.
Their housing histories could also be viewed as anomalous for two main reasons. First, the monkeys were removed from their natal groups at around age 6 months and were placed into a peer group. Second, the monkeys were, at around 3 years of age, moved into individual housing conditions for an undefined period of time. Both of these manipulations diverge from the norm for wild-ranging animals, and both can reasonably be expected to elicit varying degrees of stress and/or distress, as well as to increase the frequency of atypical, stress-related behaviors. While there are documented methods for reducing the impact of these housing conditions on monkeys, none of those techniques (notably, evidence-based use of environmental enrichment) were reportedly used here. Therefore, this study involves the examination of behavior in animals with a sociodevelopmental experience that potentially emphasizes or enriches disturbances in behavior akin to anxiety and depression, possibly explaining the relatively high occurrence of these traits in this sample.
All of these factors likely influence the expression of atypical behaviors, drawing into question the conclusion of the authors that these are spontaneous differences that could be useful in modeling human psychopathology in other settings. Rather, it is likely that at least a portion of the behaviors shown here were induced by potentially distressful and/or stressful circumstances that appear to lack adequate justification.
RE: Selection of procedures and protocols affect scientific outcomes
20 Jul 2013 at 10:43 GMTreplied to on
The etiology of mental disorders, especially of depressive disorders, remains largely unclear. A role of genetics (accounting for 40-50%), of environmental factors and of interactions between genetics and environment have been suggested in the literature. The 2 latter would account for 50 to 60% of the etiology. Environmental factors are therefore as important to investigate as genetics in the onset of depressive symptoms. (Hammen, et al. 1992, J Abnorm Psychol ; Chrousos 2009, Nat Rev Endocrinol ; Liu and Alloy 2010, Clin Psychol Rev ; Nester et al. 2002 Neuron).
The breeding farm might be considered as a naturalistic environment to long-tailed macaques regarding several wild-like features, such as mixed-gender mixed-generation social groups with a natural formation of stable ranking hierarchies and the seasonal birth of several infants. Other parameters, including weaning around 6 months of age, peer-rearing, food provisioning or the pre-shipment single-housing, are however at odds with the ecology of the species in the wild. These latter suboptimal, yet part of the common husbandry processes following ethics legislation, parameters might be rather stressful to some individuals. As adverse life events have been extensively suggested as an important risk factor for human depression, it is not aberrant to propose that a few individuals in this breeding facility might display depressive-like behaviours (Claessens, 2011, Psychopharmacol; de Kloet, 2005, Nat Rev Neurosci). Moreover the prevalence of our likely pathological animals (i.e. 10% of the observed sample displayed a depressive-like profile) is similar to the human annual prevalence of depressive disorders (i.e. 8-13% of the population). We recently published the follow-up study performed among group-housed subjects that were never single-housed and reported similar results (Camus SM, et al. (2013) Birth Origin Differentially Affects Depressive-Like Behaviours: Are Captive-Born Cynomolgus Monkeys More Vulnerable to Depression than Their Wild-Born Counterparts? PLoS ONE 8(7): e67711). The time spent in single cage alone is not sufficient to explain the atypical behaviours described here.
We introduced the “spontaneous” aspect of our study in opposition to animal models induced with invasive methods requiring direct manipulations of the individuals (genetic modifications, cerebral lesions or chronic administration of molecules). These latter models also imply captive housing conditions (most of the monkeys providing from very similar breeding farms), thereby allowing us to consider the effects of husbandry as equivalent in both models. “Spontaneous” refers to the lack of human interventions apart from the common husbandry processes, inevitable in every experimental setting.
The blood and CSF collections were of course performed by a trained and skilled veterinarian, used to work with macaques, both procedures classically performed in humans as well. They were approved by an IACUC which validated possible interference of anesthetic with monoamines. There are several examples of interference of pain-killers and anesthetic with monoamines in the literature but we would like to draw your attention to a very recent one highlighting the issue (Xie et al., 2013, Journal of Neurophysiology). These sampling were performed after the behavioural data collection and could therefore not account for the inter-individual differences reported in this study.
See the response to comment N°2 for the housing conditions. While China is the world n°1 producer of bred-macaques, the researchers, and the author of this comment, keep ignoring the conditions of breeding of animals they are likely to use at some point. We have not requested any specific conditions and have not interfered with the breeding process for conducting these studies.