The locus ceruleus: a possible neural focus for genetic differences in emotionality

The Maudsley Reactive and Non-Reactive strains have been developed as a model for the study of individual variations in stress-reactivity, and many differences in biobehavioral systems have been found between them. This review discusses limitations of the 'emotionality' construct in accounting for differences between the Maudsley strains and offers an alternative, theoretical approach. Amaral and Sinnamon have proposed that the locus ceruleus (LC) plays a stress-attenuating role in mediating behavioral, physiological and neuroendocrine response to prepotent, emergency-provoking stimuli and, building upon this formulation, it is proposed that the LC has been an important focus for gene action in the Maudsley model. It is suggested that the LC of the Non-Reactive strain is more strongly activated by stressful stimuli than the LC of Reactive rats, and is the basis of many of the behavioral and physiological differences between them. Behavioral and biochemical evidence consistent with this proposition is reviewed. Identification of the LC as a target for gene-action in the Maudsley model has an important advantage. It substitutes variations at a specific anatomic location in the brain for a loosely defined construct like emotionality, and the hypothesis is amenable to empirical tests by a variety of experimental approaches.     

The influence of cold or isolation stress on resistance of mice to West Nile virus encephalitis

The effect of cold or isolation stress on mortality rate and brain virus level were investigated in mice infected with West Nile virus (WNV). Exposure of mice for 5 min/day to cold water (1 +/- 0.5 degrees C) for 8-10 days resulted in 92% mortality as compared to 47% in control mice (p less than 0.001). Mice housed in individual cages (isolation stress) were also more susceptible to WN viral infection, as shown by increased mortality rate reaching 85% as compared to 50% in mice housed 6 per cage (p less than 0.01). Cold or isolation stress increased blood brain and spleen virus levels as early as 2 days after inoculation. After 8 days of isolation or cold stress, mice inoculated with WNV had 8.9 and 9.0 log10 plaque forming units in the brain, respectively, as compared to 6.9 in the control (p less than 0.01-0.001). Furthermore, lymphoid organs such as spleen and thymus showed severe mass loss. These data suggest that physical or non-physical stress situations enhance WNV encephalitis by accelerating virus proliferation and increase mortality in mice.     

The influence of cold or isolation stress on resistance of mice to West Nile virus encephalitis

Summary The effect of cold or isolation stress on mortality rate and brain virus level were investigated in mice infected with West Nile virus (WNV). Exposure of mice for 5 min/day to cold water (1±0.5°C) for 8–10 days resulted in 92% mortality as compared to 47% in control mice (p<0.001). Mice housed in individual cages (isolation stress) were also more susceptible to WN viral infection, as shown by increased mortality rate reaching 85% as compared to 50% in mice housed 6 per cage (p<0.01). Cold or isolation stress increased blood brain and spleen virus levels as early as 2 days after inoculation. After 8 days of isolation or cold stress, mice inoculated with WNV had 8.9 and 9.0 log₁₀ plaque forming units in the brain, respectively, as compared to 6.9 in the control (p<0.01–0.001). Furthermore, lymphoid organs such as spleen and thymus showed severe mass loss. These data suggest that physical or non-physical stress situations enhance WNV encephalitis by accelerating virus proliferation and increase mortality in mice.     

Predicting nominal variable relationships with multiple response

For forecasting purposes, it is useful to predict the most likely response of an individual to a nominally-scaled variable using the response to a predictor variable which is also nominally scaled. Traditional statistical approaches are not suitable when respondents provide multiple responses. For practical applications it is desirable to provide a simple measure of prediction that is easy to calculate and understand. Two situations are described where predictions of multiple response are implemented and two indices of predictive association are developed for the situations. These indices provide predictive explanations where none were possible using traditional methods of predictive association. The need to complement these indices with conditional probabilities and log-linear models is suggested. The evaluation and implications of these indices are discussed.     

Heritable variation for aggression as a reflection of individual coping strategies

Evidence is presented in rodents, that individual differences in aggression reflect heritable, fundamentally different, but equally valuable alternative strategies to cope with environmental demands. Generally, aggressive individuals show an active response to aversive situations. In a social setting, they react with flight or escape when defeated; in non-social situations, they react with active avoidance of controllable shocks and with sustained activity during an uncontrollable task. In contrast, non-aggressive individuals generally adopt a passive strategy. In social and non-social aversive situations, they react with immobility and withdrawal. A main aspect of these two alternative strategies is that individuals with an active strategy easily develop routines (intrinsically determined behaviour), and consequently do not react (properly) to 'minor' changes in their environment, whereas in passively reacting animals it is just the other way around (extrinsically determined behaviour). It has become clear that active and passive behavioural strategies represent two different, but equivalent, coping styles. The coping style of the aggressive males is aimed at the removal of themselves from the source of stress or at removal of the stress source itself (i.e. active manipulation). Non-aggressive individuals seem to aim at the reduction of the emotional impact of the stress (i.e. passive confrontation). The success of both coping styles depends upon the variability or stability of the environment. The fact that aggressive males develop routines may contribute to a fast execution of their anticipatory responses, which is necessary for an effective manipulation of events. However, this is only of advantage in predictable (stable) situations, but is maladaptive (e.g. expressed by the development of stress pathologies) when the animal is confronted with the unexpected (variable situations). The flexible behaviour of non-aggressive individuals, depending strongly upon external stimuli, will be of advantage under changing conditions. Studies on wild house mice living under natural conditions show how active and passive coping functions in nature, and how the two types have been brought about by natural selection.     

Depression and treatment response: dynamic interplay of signaling pathways and altered neural processes

Since the 1960s, when the first tricyclic and monoamine oxidase inhibitor antidepressant drugs were introduced, most of the ensuing agents were designed to target similar brain pathways that elevate serotonin and/or norepinephrine signaling. Fifty years later, the main goal of the current depression research is to develop faster-acting, more effective therapeutic agents with fewer side effects, as currently available antidepressants are plagued by delayed therapeutic onset and low response rates. Clinical and basic science research studies have made significant progress towards deciphering the pathophysiological events within the brain involved in development, maintenance, and treatment of major depressive disorder. Imaging and postmortem brain studies in depressed human subjects, in combination with animal behavioral models of depression, have identified a number of different cellular events, intracellular signaling pathways, proteins, and target genes that are modulated by stress and are potentially vital mediators of antidepressant action. In this review, we focus on several neural mechanisms, primarily within the hippocampus and prefrontal cortex, which have recently been implicated in depression and treatment response.     

Diagnostic and therapeutic applications of azulenyl nitrone spin traps

Azulenyl nitrones have been recently demonstrated to constitute a new class of nitrone-based spin traps with the unprecedented capacity to tag free radicals by yielding characteristically colored and highly visible diamagnetic (and paramagnetic) spin adducts. In addition, a comparison of the oxidation potentials of azulenyl nitrones such as 1 and congeners to those of conventional nitrone spin traps previously investigated as potential antioxidant therapeutics such as N-tert-butyl-alpha-phenylnitrone and its related ortho-sodium sulfonate reveals that the azulene-derived spin traps are far more readily oxidized. These special features render azulenyl nitrones of interest with regard to both their distinct ability to engender the convenient use of colorimetric detection to monitor free radical-mediated oxidative stress in biological systems, and to their potentially enhanced efficacy as neuroprotective antioxidants vs. those conventional nitrone spin traps earlier examined as such. Herein is reported an overview of recent developments pertaining to the use of azulenyl nitrones in the detection of oxidative stress in animal models of amyotrophic lateral sclerosis and stroke, and to their neuroprotective activity in animal models of Parkinson's disease, stroke and neurodegeneration within the retina.     

Transthyretin: the servant of many masters

Transthyretin (TTR) (formerly, thyroxine binding prealbumin) is an evolutionarily conserved serum and cerebrospinal fluid protein that transports holo-retinol-binding protein and thyroxine. Its serum concentration has been widely used to assess clinical nutritional status. It is also well known that wild-type transthyretin and approximately 100 different mutants give rise to a variety of forms of systemic amyloid deposition. It has been suspected and recently established that TTR can suppress the Alzheimer’s disease phenotype in transgenic animal models of cerebral Aβ deposition. Thus, while TTR is a systemic amyloid precursor, in the brain it seems to have an anti-amyloidogenic effect. TTR is found in other organs as a result of local synthesis or transport, suggesting that it may have other, as yet undiscovered, functions. It is possible that its capacity to bind many classes of compounds allows it to serve as an endogenous detoxifier of molecules with potential pathologic effects.     

The locus ceruleus: a possible neural focus for genetic differences in emotionality

Summary The Maudsley Reactive and Non-Reactive strains have been developed as a model for the study of individual variations in stress-reactivity, and many differences in biobehavioral systems have been found between them. This review discusses limitations of the emotionality construct in accounting for differences between the Maudsley strains and offers an alternative, theoretical approach. Amaral and Sinnamon have proposed that the locus ceruleus (LC) plays a stress-attenuating role in mediating behavioral, physiological and neuroendocrine response to prepotent, emergency-provoking stimuli and, building upon this formulation, it is proposed that the LC has been an important focus for gene action in the Maudsley model. It is suggested that the LC of the Non-Reactive strain is more strongly activated by stressful stimuli than the LC of Reactive rats, and is the basis of many of the behavioral and physiological differences between them. Behavioral and biochemical evidence consistent with this proposition is reviewed. Identification of the LC as a target for gene-action in the Maudsley model has an important advantage. It substitutes variations at a specific anatomic location in the brain for a loosely defined construct like emotionality, and the hypothesis is amenable to empirical tests by a variety of experimental approaches.Supported by MH-39210 from the National Institute of Mental Health to DAB     

Selected mouse lines,alcohol and behavior

Summary The technique of selective breeding has been employed to develop a number of mouse lines differing in genetic sensitivity to specific effects of ethanol. Genetic animal models for sensitivity to the hypnotic, thermoregulatory, excitatory, and dependence-producing effects of alcohol have been developed. These genetic animal models have been utilized in numerous studies to assess the bases for those genetic differences, and to determine the specific neurochemical and neurophysiological bases for ethanol's actions. Work with these lines has challenged some long-held beliefs about ethanol's mechanisms of action. For example, lines genetically sensitive to one effect of ethanol are not necessarily sensitive to others, which demonstrates that no single set of genes modulates all ethanol effects. LS mice, selected for sensitivity to ethanol anesthesia, are not similarly sensitive to all anesthetic drugs, which demonstrates that all such drugs cannot have a common mechanism of action. On the other hand, WSP mice, genetically susceptible to the development of severe ethanol withdrawal, show a similar predisposition to diazepam and phenobarbital withdrawal, which suggests that there may be a common set of genes underlying drug dependentcies. Studies with these models have also revealed important new directions for future mechanism-oriented research. Several studies implicate brain gamma-aminobutyric acid and dopamine systems as potentially important mediators of susceptibility to alcohol intoxication. The stability of the genetic animal models across laboratories and generations will continue to increase their power as analytic tools.     

Selected mouse lines, alcohol and behavior

The technique of selective breeding has been employed to develop a number of mouse lines differing in genetic sensitivity to specific effects of ethanol. Genetic animal models for sensitivity to the hypnotic, thermoregulatory, excitatory, and dependence-producing effects of alcohol have been developed. These genetic animal models have been utilized in numerous studies to assess the bases for those genetic differences, and to determine the specific neurochemical and neurophysiological bases for ethanol's actions. Work with these lines has challenged some long-held beliefs about ethanol's mechanisms of action. For example, lines genetically sensitive to one effect of ethanol are not necessarily sensitive to others, which demonstrates that no single set of genes modulates all ethanol effects. LS mice, selected for sensitivity to ethanol anesthesia, are not similarly sensitive to all anesthetic drugs, which demonstrates that all such drugs cannot have a common mechanism of action. On the other hand, WSP mice, genetically susceptible to the development of severe ethanol withdrawal, show a similar predisposition to diazepam and phenobarbital withdrawal, which suggests that there may be a common set of genes underlying drug dependencies. Studies with these models have also revealed important new directions for future mechanism-oriented research. Several studies implicate brain gamma-aminobutyric acid and dopamine systems as potentially important mediators of susceptibility to alcohol intoxication. The stability of the genetic animal models across laboratories and generations will continue to increase their power as analytic tools.     

Fibroblast growth factor 21: an overview from a clinical perspective

Fibroblast growth factor 21 (FGF21) has been proposed as a novel putative therapeutic agent in type 2 diabetes. A large amount of data, predominantly obtained from murine models but also from non-human primates, suggest that FGF21 ameliorates obesity-associated hyperglycemia and hyperlipidemia primarily via effects on adipose tissue and the pancreas. In addition, FGF21 has been reported to play a pivotal regulatory role in starvation and ketosis. However, while it is clear that FGF21 has potent effects in vivo in several animal models, the exact mechanisms remain elusive. Moreover, very recent results from different human cohort studies have shown a paradoxical regulation of plasma FGF21 in obesity and type 2 diabetes as well as other important qualitative differences in the effects and regulation of FGF21 between rodents and humans. This review focuses on the most recently published data on FGF21 with emphasis on results obtained in humans.     

Alzheimer’s disease: the impact of age-related changes in reproductive hormones

Two classes of ovarian steroids, estrogens and progestins, are potent in protecting neurons against acute toxic events as well as chronic neurodegeneration. Herein we review the evidence for neuroprotection by both classes of steroids, provide plausible mechanisms for these potent neuroprotective activities and indicate the need for further clinical trials of both estrogens and progestins in protection against acute and chronic conditions that cause neuronal death. Estrogens at concentrations ranging from physiological to pharmacological are neuroprotective in a variety of in vitro and in vivo models of cerebral ischemia and brain trauma as well as in reducing key neuropathologies of Alzheimers disease. While the mechanisms of this potent neuroprotection are currently unresolved, a mitochondrial mechanism is involved. Progestins have been recently shown to activate many of the signaling pathways used by estrogens to neuroprotect, and progestins have been shown to protect against neuronal loss in vitro and in vivo in a variety of models of acute insult. Collectively, results of these animal and tissue culture models suggest that the loss of both estrogens and progestins at the menopause makes the brain more vulnerable to acute insults and chronic neurodegenerative diseases. Further clinical assessment of appropriate regimens of estrogens, progestins and their combination are supported by these data.     

Aluminium in Alzheimer’s disease: are we still at a crossroad?

Aluminium, an environmentally abundant non-redox trivalent cation has long been implicated in the pathogenesis of Alzheimers disease (AD). However, the definite mechanism of aluminium toxicity in AD is not known. Evidence suggests that trace metal homeostasis plays a crucial role in the normal functioning of the brain, and any disturbance in it can exacerbate events associated with AD. The present paper reviews the scientific literature linking aluminium with AD. The focus is on aluminium levels in brain, region-specific and subcellular distribution, its relation to neurofibrillary tangles, amyloid beta, and other metals. A detailed mechanism of the role of aluminium in oxidative stress and cell death is highlighted. The importance of complex speciation chemistry of aluminium in relation to biology has been emphasized. The debatable role of aluminium in AD and the cross-talk between aluminium and genetic susceptibility are also discussed. Finally, it is concluded based on extensive literature that the neurotoxic effects of aluminium are beyond any doubt, and aluminium as a factor in AD cannot be discarded. However, whether aluminium is a sole factor in AD and whether it is a factor in all AD cases still needs to be understood.Received 22 July 2004; received after revision 3 September 2004; accepted 16 September 2004     

Heritable variation for aggression as a reflection of individual coping strategies

Evidence is presented in rodents, that individual differences in aggression reflect heritable, fundamentally different, but equally valuablealternative strategies to cope with environmental demands. Generally, aggressive individuals show an active response to aversive situations. In a social setting, they react with flight or escape when defeated; in non-social situations, they react with active avoidance of controllable shocks and with sustained activity during an uncontrollable task. In contrast, non-aggressive individuals generally adopt a passive strategy. In social and non-social aversive situations, they react with immobility and withdrawal.A main aspect of these two alternative strategies is that individuals with an active strategy easily develop routines (intrinsically determined behaviour), and consequently do not react (properly) to minor changes in their environment, whereas in passively reacting animals it is just the other way around (extrinsically determined behaviour). It has become clear that active and passive behavioural strategies represent two different, but equivalent, coping styles. The coping style of the aggressive males is aimed at the removal of themselves from the source of stress or at removal of the stress source itself (i. e. active manipulation). Non-aggressive individuals seem to aim at the reduction of the emotional impact of the stress (i.e. passive confrontation). The success of both coping styles depends upon the variability or stability of the environment. The fact that aggressive males develop routines may contribute to a fast excution of their anticipatory responses, which is necessary for an effective manipulation of events. However, this is only of advantage in predictable (stable) situations, but is maladaptive (e.g. expressed by the development of stress pathologies) when the animal is confronted with the unexpected (variable situations). The flexible behaviour of non-aggressive individuals, depending strongly upon external stimuli, will be of advantage under changing conditions.Studies on wild house mice living under natural conditions show how active and passive coping functions in nature, and how the two types have been brought about by natural selection.     

Genetic and environmental influences on reactive and spontaneous locomotor activities in rats

Paired groups of rats (derived from divergent, selective breeding or living in divergent environmental conditions) were compared with regard to locomotor activities. Intrapair differences were found to vary non-systematically, depending upon whether the rats were initially exposed to a test-environment with or without a slight environmental modification (reactive activities), or were allowed to habituate extensively to the environment (spontaneous activity). Since the behavioral patterns were found to represent distinct entities, this pointed to the necessity of differentiating clearly between spontaneous and reactive activities and indicated, once again, that both genetic and environmental influences are important in these behaviors and must be taken into account. Accepting and controlling for these variables makes it possible to use the factor of individual differences in laboratory animal behavior to advantage.     

Genetic and environmental influences on reactive and spontaneous locomotor activities in rats

Paired groups of rats (derived from divergent, selective breeding or living in divergent environmental conditions) were compared with regard to locomotor activities. Intrapair differences were found to vary non-systematically, depending upon whether the rats were initially exposed to a test-environment with or without a slight environmental modification (reactive activities), or were allowed to habituate extensively to the environment (spontaneous activity). Since the behavioral patterns were found to represent distinct entities, this pointed to the necessity of differentiating clearly between spontaneous and reactive activities and indicated, once again, that both genetic and environmental influences are important in these behaviors and must be taken into account. Accepting and controlling for these variables makes it possible to use the factor of individual differences in laboratory animal behavior to advantage.     

The AA and ANA rat lines, selected for differences in voluntary alcohol consumption

The offspring of rats that voluntarily select larger quantities of alcohol are heavier consumers of alcohol than the offspring of rats that tend to avoid it. Such selective breeding, repeated over many generations, was used to develop the AA (Alko, Alcohol) line of rats which prefer 10% alcohol to water, and the ANA (Alko, Non-Alcohol) line of rats which choose water to the virtual exclusion of alcohol. In addition to demonstrating the likely role of genetic factors in alcohol consumption, these lines have been used to find behavioral, metabolic, and neurochemical correlates of differential alcohol intake. Some of the line differences that have been found involve the reinforcing effects of ethanol, the changes in consumption produced by alcohol deprivation and nutritional factors, the behavioral and adrenal monoamine reactions to mild stress, the development of tolerance, the accumulation of acetaldehyde during ethanol metabolism, and the brain levels of serotonin. It is hoped that these studies will lead to a better understanding of the genetically-determined mechanisms that influence the selection of alcohol.     

The AA and ANA rat lines,selected for differences in voluntary alcohol consumption

Summary The offspring of rats that voluntarily select larger quantities of alcohol are heavier consumers of alcohol than the offspring of rats that tend to avoid it. Such selective breeding, repeated over many generations, was used to develop the AA (Alko, Alcohol) line of rats which prefer 10% alcohol to water, and the ANA (Alko, Non-Alcohol) line of rats which choose water to the virtual exclusion of alcohol. In addition to demonstrating the likely role of genetic factors in alcohol consumption, these lines have been used to find behavioral, metabolic, and neurochemical correlates of differential alcohol intake. Some of the line differences that have been found involve the reinforcing effects of ethanol, the changes in consumption produced by alcohol deprivation and nutritional factors, the behavioral and adrenal monoamine reactions to mild stress, the development of tolerance, the accumulation of acetaldehyde during ethanol metabolism, and the brain levels of serotonin. It is hoped that these studies will lead to a better understanding of the genetically-determined mechanisms that influence the selection of alcohol.     

Using genetically-defined rodent strains for the identification of hippocampal traits relevant for two-way avoidance behavior: a non-invasive approach

Genetically-defined rodent strains permit the identification of hippocampal traits which are of functional relevance for the performance of two-way avoidance behavior. This is exemplified here by analyzing the relationship between infrapyramidal mossy fibers (a tiny projection terminating upon the basal dendrites of hippocampal pyramidal neurons) and two-way avoidance learning in about 800 animals. The necessary steps include 1) identification of structural traits sensitive to selective breeding for extremes in two-way avoidance, 2) testing the robustness of the associations found by studying individual and genetical correlations between hippocampal traits and behavior, 3) establishing causal relationships by Mendelian crossing of strains with extreme structural traits and studying the behavioral consequences of such structural 'randomization', 4) confirming causal relationships by manipulating the structural variable in inbred (isogenic) strains, thereby eliminating the possibility of genetic linkage, and 5) ruling out the possibility of spurious associations by studying the correlations between the hippocampal trait and other behaviors known to depend on hippocampal functioning. In comparison with the classical lesion approach for identifying relationships between brain and behavior, the present procedure appears to be superior in two aspects: it is non-invasive, and it focuses automatically on those brain traits which are used by natural selection to shape behaviorally-defined animal populations, i.e., it reveals the natural regulators of behavior.