Manganese (Mn) is an essential element but neurotoxic at higher exposure levels. The effects of Mn overexposure (MnOE) on hippocampal and striatal-dependent learning and memory in rats were tested in combination with iron deficiency (FeD) and developmental stress that often co-occur with MnOE. Moderate FeD affects up to 15% of U.S. children and developmental stress is common in lower socio-economic areas where MnOE occurs. Pregnant Sprague-Dawley rats and their litters were housed in cages with or without (barren cage (BAR)) standard bedding from embryonic day (E)7 to postnatal day (P)28. Dams were fed a 90% FeD or iron sufficient (FeS) diet from E15-P28. Within each litter, separate offspring were treated with 100 mg/kg Mn (MnOE) or vehicle (VEH) by gavage on alternate days from P4-28. Offspring were tested as adults in the Morris and Cincinnati water mazes. FeD and developmental stress interactively impaired spatial learning in the Morris water maze. Developmental stress and MnOE impaired learning and memory in both mazes. MnOE resulted in reduced CA1 hippocampal long-term potentiation (LTP) and increased levels of α-synuclein. Preweaning MnOE results in cognitive deficits on multiple domains of learning and memory accompanied by impaired LTP and α-synuclein changes, effects worsened by developmental stress.

This paper responds to a recent challenge for the validity of extrapolation of neurobiological knowledge from laboratory animals to humans. According to this challenge, experimental neurobiology, and thus neuroscience, is in a state of crisis because the knowledge produced in different laboratories hardly generalizes from one laboratory to another. Presumably, this is so because neurobiological laboratories use simplified animal models of human conditions that differ across laboratories. By contrast, I argue that maintaining a multiplicity of experimental protocols and simple models is well justified. It fosters rather than precludes the validity of extrapolation of neurobiological knowledge. The discipline is thriving.Keywords: Animal Models, Calibration, Validity, Reliability, Experimental Neurobiology.RESUMEN: Este artículo responde a un reto reciente: la validez de extrapolar el conocimiento neurobiológico del laboratorio animal a los humanos. Según esta objeción la neurobiología experimental, y por ende la neurociencia, está en crisis porque el conocimiento obtenido en los laboratorios de neurobiología utiliza modelos animales simplificados de las condiciones humanas que difieren de unos laboratorios a otros. Por el contrario, sostengo que mantener una diversidad de protocolos experimentales y de modelos simples está sobradamente justificado. Favorece, en vez de impedir, la validez de la extrapolación de conocimiento neurobiológico. La neurobiología es una disciplina floreciente.

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The 'new mechanists' assume that discovering neural mechanisms is a major aim of neuroscience where this constitutes a process of explaining. They strive to articulate the norms for good explanations. I argue that: the normative project of the ontic mechanistic explanation is unrealistic; the epistemological version of mechanistic explanation accounts for the practical epistemological constraints of neuroscience but fails normatively; hence a dilemma: either methodologically strong but unrealistic or epistemologically realistic but methodologically weak view of mechanistic explanation. I propose that the solution is in abandoning the idea that the study of mechanisms in neuroscience aims mainly at explaining. Model-building and simulating neural phenomena and mechanisms do not necessarily aim at providing explanations. Additionally, some of the cognitive goals attributed to explanation are actually served by simulation. Thus, the new mechanist approach needs to be revised so as to do better justice to the role of simulation in neuroscience.