5-HT1A Receptors on Dentate Gyrus Granule Cells Confer Stress Resilience.

BACKGROUND: Hyperactivity of granule cells in the ventral dentate gyrus (vDG) promotes vulnerability to chronic stress. However, which receptors in the vDG could be targeted to inhibit this hyperactivity and confer stress resilience is not known. The serotonin 1A receptor (5-HT1AR) is a Gi protein-coupled inhibitory receptor that has been implicated in stress adaptation, anxiety, depression, and antidepressant responses. 5-HT1ARs are highly expressed in the DG, but their potential to promote stress resilience by regulating granule cell activity has never been examined. METHODS: We exposed male and female mice expressing 5-HT1ARs only in DG granule cells to 10 days of chronic social defeat stress (CSDS) and treated them with the 5-HT1AR agonist 8-OH-DPAT every day 30 minutes before each defeat throughout the CSDS paradigm. We then used whole-cell current clamp recordings, immunohistochemistry for the immediate early gene cFos, corticosterone immunoassays, and behavioral testing to determine how activating 5-HT1ARs on granule cells affects DG activity, neuroendocrine stress responses, and avoidance behavior. RESULTS: We found that activating 5-HT1ARs hyperpolarized DG granule cells and reduced cFos+ granule cells in the vDG following CSDS, indicating that 5-HT1AR activation rescued stress-induced vDG hyperactivity. Moreover, 5-HT1AR activation dampened corticosterone responses to CSDS and prevented the development of stress-induced avoidance in the social interaction test and in the open field test. CONCLUSIONS: Our findings show that activating 5-HT1ARs on DG granule cells can prevent stress-induced neuronal hyperactivity of the vDG and confer resilience to chronic stress.

Hodgkin's and Huxley's own assessments of their "quantitative description" of nerve membrane current.

Alan Hodgkin's and Andrew Huxley's mid-20th century work on the ionic currents generating neuron action potentials stands among that century's great scientific achievements. Unsurprisingly, that case has attracted widespread attention from neuroscientists, historians and philosophers of science. In this paper, I do not propose to add any new insights into the vast historical treatment of Hodgkin's and Huxley's scientific discoveries in that much- discussed episode. Instead, I focus on an aspect of it that hasn't received much attention: Hodgkin's and Huxley's own assessments about what their famous "quantitative description" accomplished. The "Hodgkin-Huxley model" is now widely recognized as a foundation of contemporary computational neuroscience. Yet Hodgkin and Huxley expressed serious caveats about their model and what it added to their scientific discoveries, as far back as their (1952d), in which they first presented their model. They were even more critical of its accomplishments in their Nobel Prize addresses a decade later. Most notably, as I argue here, some worries they raised about their quantitative description seem still to be relevant to current work in ongoing computational neuroscience.

New research tools suggest a "levels-less" image of the behaving organism and dissolution of the reduction vs. anti-reduction dispute.

A kind of "ruthless reductionism" characterized the experimental practices of the first two decades of molecular and cellular cognition (MCC). More recently, new research tools have expanded experimental practices in this field, enabling researchers to image and manipulate individual molecular mechanisms in behaving organisms with an unprecedented temporal, sub-cellular, cellular, and even circuit-wide specificity. These tools dramatically expand the range and reach of experiments in MCC, and in doing so they may help us transcend the worn-out and counterproductive debates about "reductionism" and "emergence" that divide neuroscientists and philosophers alike. We describe examples of these new tools and illustrate their practical power by presenting an exemplary recent case of MCC research using them. From these tools and results, we provide an initial sketch of a new image of the behaving organism in its full causal-interactive complexity, with its molecules, cells, and circuits combined within the single system that it is. This new image stands in opposition to the traditional "levels" image of the behaving organism, and even the initial sketch we provide of it here offers hope for avoiding the dreary metaphysical debates about "emergence" and "downward causation," and even the reduction vs. anti-reduction dispute, all dependent upon the familiar "levels" image.

When should researchers cite study differences in response to a failure to replicate?

Scientists often respond to failures to replicate by citing differences between the experimental components of an original study and those of its attempted replication. In this paper, we investigate these purported mismatch explanations. We assess a body of failures to replicate in neuroscience studies on spinal cord injury. We argue that a defensible mismatch explanation is one where (1) a mismatch of components is a difference maker for a mismatch of outcomes, and (2) the components are relevantly different in the follow-up study, given the scope of the original study. With this account, we argue that not all differences between studies are meaningful, even if they are difference makers. As our examples show, focusing only on these differences results in disregarding the representativeness of the original experiment's components and the scope of its outcomes, undercutting other epistemic aims, such as translation, in the process.

The first two decades of CREB-memory research: data for philosophy of neuroscience.

I recount some landmark discoveries that initially confirmed the cyclic AMP response element-binding (CREB) protein-memory consolidation and allocation linkages. This work constitutes one of the successes of the field of Molecular and Cellular Cognition (MCC) but is also of interest to philosophers of neuroscience. Two approaches, "mechanism" and "ruthless reductionism", claim to account for this case, yet these accounts differ in one crucial way. I explain this difference and argue that both the experiment designs and discussions of these discoveries by MCC scientists better fit the ruthless reductionist's account. This conclusion leads to further philosophical discussion about how discoveries in cellular/molecular neurobiology integrate with systems neuroscience findings.

Laser Lights and Designer Drugs: New Techniques for Descending Levels of Mechanisms "in a Single Bound"?

Optogenetics and DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are important research tools in recent neurobiology. These tools allow unprecedented control over activity in specifically targeted neurons in behaving animals. Two approaches in philosophy of neuroscience, mechanism and ruthless reductionism, provide explicit accounts of experiments and results using tools like these, but each offers a different picture about how levels of mechanisms relate. I argue here that the ruthless reductionist's direct mind-to-cellular/molecular activities linkages "in a single bound" better fits with both the experimental designs using these tools and some of the scientists' own judgments about their results than does the mechanist's "nested hierarchies of mechanisms-within-mechanisms." So at least some important work in current neuroscience appears to be ruthlessly reductive. Mechanism may not correctly characterize all current work in neuroscience, despite its recent popularity.

Revolutions in Neuroscience: Tool Development.

Thomas Kuhn's famous model of the components and dynamics of scientific revolutions is still dominant to this day across science, philosophy, and history. The guiding philosophical theme of this article is that, concerning actual revolutions in neuroscience over the past 60 years, Kuhn's account is wrong. There have been revolutions, and new ones are brewing, but they do not turn on competing paradigms, anomalies, or the like. Instead, they turn exclusively on the development of new experimental tools. I adopt a metascientific approach and examine in detail the development of two recent neuroscience revolutions: the impact of engineered genetically mutated mammals in the search for causal mechanisms of "higher" cognitive functions; and the more recent impact of optogenetics and designer receptors exclusively activated by designer drugs (DREADDs). The two key metascientific concepts, I derive from these case studies are a revolutionary new tool's motivating problem, and its initial and second-phase hook experiments. These concepts hardly exhaust a detailed metascience of tool development experiments in neuroscience, but they get that project off to a useful start and distinguish the subsequent account of neuroscience revolutions clearly from Kuhn's famous model. I close with a brief remark about the general importance of molecular biology for a current philosophical understanding of science, as comparable to the place physics occupied when Kuhn formulated his famous theory of scientific revolutions.

Marr and reductionism.

David Marr's three-level method for completely understanding a cognitive system and the importance he attaches to the computational level are so familiar as to scarcely need repeating. Fewer seem to recognize that Marr defends his famous method by criticizing the "reductionistic approach." This sets up a more interesting relationship between Marr and reductionism than is usually acknowledged. I argue that Marr was correct in his criticism of the reductionists of his time-they were only describing (cellular activity), not explaining (cognitive functions). But a careful metascientific account of reductionistic neuroscience over the past two decades reveals that Marr's criticisms no longer have force. Contemporary neuroscience now explains cognition directly, although in a fashion-causal-mechanistically-quite different than Marr recommended. So while Marr was correct to reject the reductionism of his day and offer an alternative method for genuinely explaining cognition, contemporary cognitive scientists now owe us a new defense of Marr's famous method and the advantages of its explanations over the type now pursued successfully in current reductionist neuroscience. There are familiar reasons for thinking that this debt will not be paid easily.

The molecules of social recognition memory: implications for social cognition, extended mind, and neuroethics.

Social cognition, cognitive neuroscience, and neuroethics have reached a synthesis of late, but some troubling features are present. The neuroscience that currently dominates the study of social cognition is exclusively cognitive neuroscience, as contrasted with the cellular and increasingly molecular emphasis that has gripped mainstream neuroscience over the past three decades. Furthermore, the recent field of molecular and cellular cognition has begun to unravel some molecular mechanisms involved in social cognition, especially pertaining to the consolidation of memories of particular conspecific organisms. Some new experimental techniques for positive interventions into these hypothesized mechanisms offer opportunities for establishing direct causal linkages between intra-neuronal molecular events and the behaviors used to measure social cognitive phenomena. Predicted results from an experiment described below also cast doubt on the application of the "extended mind" approach from recent cognitive science to ground the neuroscience of social cognition. Since neuroethics relies heavily on our best neuroscience of social cognition, that field may soon need to extend its attention beyond cognitive neuroscience, and into neuroscience's cellular and molecular mainstream.

Ruthless reductionism and social cognition.

Social cognition appears to present phenomena that "ruthlessly reductive" molecular and cellular neuroscience cannot fruitfully investigate or explain. This is because the causes of such phenomena are distal and external not only to the molecular machinery of individual neurons, but to individual brains. However, the "reductionist's epiphany" insists that to the extent that we understand the specific molecular mechanisms that underlie phenomena upon which most or all social cognition depends, we can be sure that molecular mechanisms for the broader phenomena can be found using standard experimental methods from molecular and cellular cognition. Furthermore, social recognition memory consolidation is required for virtually all types of social cognition, and its specific molecular mechanisms have now been uncovered experimentally. These same molecular mechanisms obtain across a wide variety of divergent species (from invertebrates to vertebrates). Thus we can expect to find the molecular mechanisms of the broader social cognitive functions that must "plug into" these specific molecular mechanisms, despite these functions' typically distal, external initial causes. This conclusion rests on explicit scientific facts, not just on some vague philosophical commitment to physicalism about mind.