Yann S. Mineur

It is not ''either/or'': Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood

Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is to what extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both these processes to nicotine-mediated behaviors. For instance, desensitization of nAChRs may contribute to the salience of environmental cues associated with smoking behavior and activation and desensitization of nAChRs may contribute to both primary and conditioned drug reward. Similarly, studies of the antidepressant-like effects of nicotinic agents have revealed a balance between activation and desensitization of nAChRs. This review will examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine addiction, including processes related to drug reinforcement and affective modulation. We conclude that there are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in tobacco smoking.

Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior

Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors.

Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice.

The widely accepted stress-diathesis hypothesis of depression postulates that genetic factors contribute to biological vulnerability. Based on this concept, the unpredictable chronic mild stress (UCMS) animal model was developed. Most effects of UCMS can be reversed by antidepressant agents, illustrating a strong predictive validity. In rodents, UCMS also has good face validity as it can elicit depression-like symptoms. While abundant for rats, the UCMS literature on mice is relatively limited. Reports sometimes are contradictory, making it difficult to establish a clear profile of stress-induced depression-like behaviors in mice. As different groups often use different strains for their experiments, differential strain susceptibility to UCMS may provide at least a partial explanation of these discrepancies. Moreover, differences in testing methodology add another level of complexity. Very little is known about the role of genetic factors and their interactions with the environment in the development of stress-induced behavioral changes relevant to depression, though recent studies unequivocally demonstrated the effects of specific gene polymorphisms on stress-induced depressive symptoms, as well as the effects of stress on gene expression. In the present study, we investigated the effects of UCMS on a battery of different tests measuring anxiety and depression-like behaviors in three behaviorally and genetically distinct inbred strains. The goals of these experiments are to obtain a clearer behavioral profile of genetically/phenotypically distant mouse strains after UCMS treatment and to evaluate the limitations and strengths of the UCMS model in mice.

Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis.

There is a well-established connection between smoking and depression. Depressed individuals are over-represented among smokers, and ex-smokers often experience increased depressive symptoms immediately after stopping smoking. Nicotine in tobacco binds, activates and desensitizes nicotinic acetylcholine receptors (nAChRs), but it is not known whether activation or desensitization is more important for the effects of nicotine on depressive symptoms. Here we review, based on clinical and preclinical studies of nicotinic drugs, the hypothesis that blockade (rather than activation) of neuronal nAChRs might be important for the effects of nicotinic agents on depressive symptoms. The endogenous neurotransmitter for nAChRs is acetylcholine, and the effects of nicotine on depression-like behaviors support the idea that dysregulation of the cholinergic system might contribute to the etiology of major depressive disorder. Thus, pharmacological agents that limit acetylcholine signaling through neuronal nAChRs might be promising for the development of novel antidepressant medications.

Social behavior deficits in the Fmr1 mutant mouse.

Mice exhibiting deficits in social behavior may provide valuable models for autistic-like behavioral problems. We tested social interactions in male mice from three inbred strains: C57BL/6J (B6), BALB/cJ (C) and DBA/2J (D2). All three strains showed gradual habituation of the number of social interactions with an ovariectomized female over four subsequent 2min sessions, returning to initial levels when presented with another stimulus mouse. Next, we studied males with a knockout mutation in the Fmr1 gene on a B6 background. KO animals showed strongly reduced levels of social interaction, which were about similar as those of habituated controls. This social behavior deficit suggests that Fmr1 KO mice could possibly be used as models for autistic behaviors.

Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior

Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety- and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety- and depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety- and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.

Agonistic Behavior and Unpredictable Chronic Mild Stress in Mice

A significant proportion of patients suffering from major clinical depression exhibit sudden bursts of anger often described as “panic attacks without anxiety or fear” or “irritability.” We investigated aggressive behavior in mice from four different inbred strains subjected to unpredictable chronic mild stress (UCMS). Our results show that UCMS affects self-grooming behavior, as evaluated by the state of an animals fur, with severity of symptoms differing according to genetic background. Furthermore, UCMS increased aggression both in a resident-intruder test and between cage-mates. UCMS is therefore a valuable model of the problematic aggressive behavior seen in depressive patients.

Antidepressant-Like Effects of Ceftriaxone in Male C57BL/6J Mice

BACKGROUND Excessive glutamatergic neurotransmission is hypothesized to be associated with depressive-like behaviors and possibly major depressive disorder (MDD). Recent evidence that beta-lactam antibiotic agents stimulate uptake of glutamate suggests that this class of compounds might possess antidepressant-like activity. METHODS Three-month old, male, C57BL/6J mice were administered ceftriaxone (200 mg/kg IP) for 14-18 days, then tested in the tail-suspension, forced swim, and novelty-suppressed feeding tests to determine whether ceftriaxone had similar effects to classical antidepressant compounds in these models. RESULTS Ceftriaxone treatment had an antidepressant-like effect across models. Reduced immobility and decreased freezing were observed in the forced swim and tail suspension tests. The same trend was seen in novelty-suppressed feeding, but the effect was not statistically significant. CONCLUSION Ceftriaxone demonstrates antidepressant-like effects in several mouse models. This is consistent with the hypothesis that enhanced uptake of glutamate might have antidepressant-like effects.

Functional implications of decreases in neurogenesis following chronic mild stress in mice.

Numerous data from human and animal studies suggest that hippocampal plasticity might be a key element in depression. However, the connection remains loose at best and further data are needed. Human studies are of necessity limited, but animal models can help providing further insight. Unpredictable chronic mild stress (UCMS) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients. We therefore studied learning and hippocampal neurogenesis in mice from three different inbred strains subjected to UCMS. Learning was assessed in different hippocampus-dependent and independent tasks. The rate of survival of newly generated brain cells was determined in behaviorally-naive animals. Results demonstrated a dramatic reduction of surviving new brain cells in both the hippocampus and the subventricular zone of UCMS-treated animals. This reduction was observed both for neurons and for other cells of the hippocampus. Behavioral data demonstrated an impairment of hippocampus-dependent learning, whereas hippocampus-independent learning was spared. However, the specific results were strongly dependent on strain and sex so that there does not appear to be a direct causative relationship between the deficits in neurogenesis and behavior.

An instructive role for patterned spontaneous retinal activity in mouse visual map development.

Complex neural circuits in the mammalian brain develop through a combination of genetic instruction and activity-dependent refinement. The relative role of these factors and the form of neuronal activity responsible for circuit development is a matter of significant debate. In the mammalian visual system, retinal ganglion cell projections to the brain are mapped with respect to retinotopic location and eye of origin. We manipulated the pattern of spontaneous retinal waves present during development without changing overall activity levels through the transgenic expression of β2-nicotinic acetylcholine receptors in retinal ganglion cells of mice. We used this manipulation to demonstrate that spontaneous retinal activity is not just permissive, but instructive in the emergence of eye-specific segregation and retinotopic refinement in the mouse visual system. This suggests that specific patterns of spontaneous activity throughout the developing brain are essential in the emergence of specific and distinct patterns of neuronal connectivity.