Hans A. Hofmann

The vertebrate mesolimbic reward system and social behavior network: a comparative synthesis.

All animals evaluate the salience of external stimuli and integrate them with internal physiological information into adaptive behavior. Natural and sexual selection impinge on these processes, yet our understanding of behavioral decision‐making mechanisms and their evolution is still very limited. Insights from mammals indicate that two neural circuits are of crucial importance in this context: the social behavior network and the mesolimbic reward system. Here we review evidence from neurochemical, tract‐tracing, developmental, and functional lesion/stimulation studies that delineates homology relationships for most of the nodes of these two circuits across the five major vertebrate lineages: mammals, birds, reptiles, amphibians, and teleost fish. We provide for the first time a comprehensive comparative analysis of the two neural circuits and conclude that they were already present in early vertebrates. We also propose that these circuits form a larger social decision‐making (SDM) network that regulates adaptive behavior. Our synthesis thus provides an important foundation for understanding the evolution of the neural mechanisms underlying reward processing and behavioral regulation. J. Comp. Neurol. 519:3599–3639, 2011.

The genomic substrate for adaptive radiation in African cichlid fish

Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification.

Biologically meaningful expression profiling across species using heterologous hybridization to a cDNA microarray

BackgroundUnravelling the path from genotype to phenotype, as it is influenced by an organisms environment, is one of the central goals in biology. Gene expression profiling by means of microarrays has become very prominent in this endeavour, although resources exist only for relatively few model systems. As genomics has matured into a comparative research program, expression profiling now also provides a powerful tool for non-traditional model systems to elucidate the molecular basis of complex traits.ResultsHere we present a microarray constructed with ~4500 features, derived from a brain-specific cDNA library for the African cichlid fish Astatotilapia burtoni (Perciformes). Heterologous hybridization, targeting RNA to an array constructed for a different species, is used for eight different fish species. We quantified the concordance in gene expression profiles across these species (number of genes and fold-changes). Although most robust when target RNA is derived from closely related species (<10 MA divergence time), our results showed consistent profiles for other closely related taxa (~65 MA divergence time) and, to a lesser extent, even very distantly related species (>200 MA divergence time).ConclusionThis strategy overcomes some of the restrictions imposed on model systems that are of importance for evolutionary and ecological studies, but for which only limited sequence information is available. Our work validates the use of expression profiling for functional genomics within a comparative framework and provides a foundation for the molecular and cellular analysis of complex traits in a wide range of organisms.

The Fight and Flight Responses of Crickets Depleted of Biogenic Amines

Aggressive and escape behaviors were analysed in crickets (Orthoptera) treated with either reserpine, a nonspecific depleter of biogenic amines, or the synthesis inhibitors alpha-methyltryptophan (AMTP) and alpha-methyl-p-tyrosine (AMT) to specifically deplete serotonin, respectively dopamine and octopamine. Standard immunocytochemical techniques were used to verify depletion from central nervous tissue, and determine the effective dosages. Reserpinized crickets became exceedingly lethargic and had severely depressed escape responses. However, they were still able to express all the major elements of the escalating sequences of stereotype motor performances that typifies normal aggressive behavior in the cricket. AMT and AMTP treatment had opposing influences on escape behavior, being enhanced by serotonin depletion, but depressed by dopamine/octopamine depletion. AMTP-induced serotonin depletion had no influence on aggressive or submissive behaviors. AMT-treated crickets could normally only be brought to fight by coaxing. Though capable of expressing aggressive behavior per se, agonistic encounters between AMT-treated crickets were shorter, and rarely involved actual physical interactions. Hence, although amines seem to have similar actions on escape behavior in insects and crustaceans, the aminergic control of aggression seems to be fundamentally different in these arthropods groups. We conclude that amines are not in principle required for the initiation and operation of the motor circuits underlying aggression in the cricket. However, octopamine and/or dopamine seem necessary for establishing a level of excitability sufficient for aggressive behavior to become overt in response to appropriate natural releasing stimuli.

Expression of arginine vasotocin in distinct preoptic regions is associated with dominant and subordinate behaviour in an African cichlid fish

Neuropeptides have widespread modulatory effects on behaviour and physiology and are associated with phenotypic transitions in a variety of animals. Arginine vasotocin (AVT) is implicated in mediating alternative male phenotypes in teleost fish, but the direction of the association differs among species, with either higher or lower AVT related to more territorial behaviour in different fishes. To clarify the complex relationship between AVT and alternative phenotype, we evaluated AVT expression in an African cichlid in which social status is associated with divergent behaviour and physiology. We compared AVT mRNA expression between territorial and non-territorial (NT) males in both whole brains and microdissected anterior preoptic areas using transcription profiling, and in individual preoptic nuclei using in situ hybridization. These complementary methods revealed that in the posterior preoptic area (gigantocellular nucleus), territorial males exhibit higher levels of AVT expression than NT males. Conversely, in the anterior preoptic area (parvocellular nucleus), AVT expression is lower in territorial males than NT males. We further correlated AVT expression with behavioural and physiological characteristics of social status to gain insight into the divergent functions of individual AVT nuclei. Overall, our findings highlight a complex association between AVT and social behaviour.

Environmental complexity and social organization sculpt the brain in Lake Tanganyikan cichlid fish.

Complex brains and behaviors have occurred repeatedly within vertebrate classes throughout evolution. What adaptive pressures drive such changes? Both environmental and social features have been implicated in the expansion of select brain structures, particularly the telencephalon. East African cichlid fishes provide a superb opportunity to analyze the social and ecological correlates of neural phenotypes and their evolution. As a result of rapid, recent, and repeated radiations, there are hundreds of closely-related species available for study, with an astonishing diversity in habitat preferences and social behaviors. In this study, we present quantitative ecological, social, and neuroanatomical data for closely-related species from the (monophyletic) Ectodini clade of Lake Tanganyikan cichlid fish. The species differed either in habitat preference or social organization. After accounting for phylogeny with independent contrasts, we find that environmental and social factors differentially affect the brain, with environmental factors showing a broader effect on a range of brain structures compared to social factors. Five out of seven of the brain measures show a relationship with habitat measures. Brain size and cerebellar size are positively correlated with species number (which is correlated with habitat complexity); the medulla and olfactory bulb are negatively correlated with habitat measures. The telencephalon shows a trend toward a positive correlation with rock size. In contrast, only two brain structures, the telencephalon and hypothalamus, are correlated with social factors. Telencephalic size is larger in monogamous species compared to polygamous species, as well as with increased numbers of individuals; monogamy is also associated with smaller hypothalamic size. Our results suggest that selection or drift can act independently on different brain regions as the species diverge into different habitats and social systems.

Alternative life histories shape brain gene expression profiles in males of the same population

Atlantic salmon (Salmo salar) undergo spectacular marine migrations before homing to spawn in natal rivers. However, males that grow fastest early in life can adopt an alternative ‘sneaker’ tactic by maturing earlier at greatly reduced size without leaving freshwater. While the ultimate evolutionary causes have been well studied, virtually nothing is known about the molecular bases of this developmental plasticity. We investigate the nature and extent of coordinated molecular changes that accompany such a fundamental transformation by comparing the brain transcription profiles of wild mature sneaker males to age-matched immature males (future large anadromous males) and immature females. Of the ca. 3000 genes surveyed, 15% are differentially expressed in the brains of the two male types. These genes are involved in a wide range of processes, including growth, reproduction and neural plasticity. Interestingly, despite the potential for wide variation in gene expression profiles among individuals sampled in nature, consistent patterns of gene expression were found for individuals of the same reproductive tactic. Notably, gene expression patterns in immature males were different both from immature females and sneakers, indicating that delayed maturation and sea migration by immature males, the ‘default’ life cycle, may actually result from an active inhibition of development into a sneaker.

Fish and chips: functional genomics of social plasticity in an African cichlid fish

SUMMARY Behavior and physiology are regulated by both environment and social context. A central goal in the study of the social control of behavior is to determine the underlying physiological, cellular and molecular mechanisms in the brain. The African cichlid fish Astatotilapia burtoni has long been used as a model system to study how social interactions regulate neural and behavioral plasticity. In this species, males are either socially dominant and reproductively active or subordinate and reproductively suppressed. This phenotypic difference is reversible. Using an integrative approach that combines quantitative behavioral measurements, functional genomics and bioinformatic analyses, we examine neural gene expression in dominant and subordinate males as well as in brooding females. We confirm the role of numerous candidate genes that are part of neuroendocrine pathways and show that specific co-regulated gene sets (modules), as well as specific functional gene ontology categories, are significantly associated with either dominance or reproductive state. Finally, even though the dominant and subordinate phenotypes are robustly defined, we find a surprisingly high degree of individual variation in the transcript levels of the very genes that are differentially regulated between these phenotypes. The results of the present study demonstrate the molecular complexity in the brain underlying social behavior, identify novel targets for future studies, validate many candidate genes and exploit individual variation in order to gain biological insights.

Genes, hormones, and circuits: an integrative approach to study the evolution of social behavior.

Tremendous progress has been made in our understanding of the ultimate and proximate mechanisms underlying social behavior, yet an integrative evolutionary analysis of its underpinnings has been difficult. In this review, we propose that modern genomic approaches can facilitate such studies by integrating four approaches to brain and behavior studies: (1) animals face many challenges and opportunities that are ecologically and socially equivalent across species; (2) they respond with species-specific, yet quantifiable and comparable approach and avoidance behaviors; (3) these behaviors in turn are regulated by gene modules and neurochemical codes; and (4) these behaviors are governed by brain circuits such as the mesolimbic reward system and the social behavior network. For each approach, we discuss genomic and other studies that have shed light on various aspects of social behavior and its underpinnings and suggest promising avenues for future research into the evolution of neuroethological systems.

Sexual and social stimuli elicit rapid and contrasting genomic responses

Sensory physiology has been shown to influence female mate choice, yet little is known about the mechanisms within the brain that regulate this critical behaviour. Here we examine preference behaviour of 58 female swordtails, Xiphophorus nigrensis, in four different social environments (attractive and unattractive males, females only, non-attractive males only and asocial conditions) followed by neural gene expression profiling. We used a brain-specific cDNA microarray to identify patterns of genomic response and candidate genes, followed by quantitative PCR (qPCR) examination of gene expression with variation in behaviour. Our microarray results revealed patterns of genomic response differing more between classes of social stimuli than between presence versus absence of stimuli. We identified suites of genes showing diametrically opposed patterns of expression: genes that are turned ‘on’ while females interact with attractive males are turned ‘off’ when interacting with other females, and vice versa. Our qPCR results identified significant predictive relationships between five candidate genes and specific mate choice behaviours (preference and receptivity) across females exposed to males, with no significant patterns identified in female or asocial conditions or with overall locomotor activity. The identification of stimulus- and behaviour-specific responses opens an exciting window into the molecular pathways associated with social behaviour and mechanisms that underlie sexual selection.