A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures

In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders. We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced adaptations dissipate (the “time-off seizure” effect), leading to the re-emergence of seizures, a re-induction of a new, but diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats, an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance. We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive (decreasing the stimulation current.), increasing drug dosage, switching to a new drug that does not show crosstolerance to the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal. Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent illness emergence and progression and its associated accumulating neurobiological, vulnerability factors.     

Adaptive strategies in natural populations of Drosophila

Summary Adult tolerance of ethanol vapour in a closed system containing 12% ethanol in solution, decreases in a cline from southern to northern Australia. However a Darwin population is more tolerant than predicted from its latitude. Ethanol tolerance races in Australia have almost certainly evolved within the last 100–150 years, because of resource unavailability prior to that time. Within populations, variation among isofemale strains is lowest in the climatically extreme southern Melbourne (37°S) and northern Darwin and Melville I. (11–12°S) populations. This suggests low resource diversity within extreme populations compared with the climatically less extreme Brisbane (28°S) and especially Townsville (19°S) populations. For desiccation resistance, the population rankings are: Darwin Melbourne > Townsville > Brisbane Melville I. and for development time, rankings are similar: Darwin Melbourne < Townsville < Brisbane Melville I.Therefore resource utilization heterogeneity is greatest in populations not greatly stressed by desiccation and where development times are extended. In total therefore, the utilization of a diversity of resources is a feature of populations tending somewhat towards a K-strategy; this is emphasized by the relative heterogeneity among isofemale strains of these populations for desiccation resistance and to a lesser extent development times.The D. melanogaster gene pool can be viewed as made up of climate-associated races. Since the ethanol tolerances of adjacent (and climatically similar) Darwin and Melville I. are very different, resource utilization races may occur within climatic races. Such a mosaic of resource utilization races are more likely in climatically extreme than in optimal habitats.     

On the Green’s function for a one-dimensional random walk

The Green’s function of a random walk on a lattice is defined as the inverse of the operatorK-z1, whereK is the matrix of transition rates and z is an arbitrary complex parameter. The Green’s function for a symmetrical random walk in one dimension is here explicitly given in closed form for reflecting, periodic, and absorbing boundaries, and also for an infinite lattice.     

Phylogeography of the last surviving populations of Rhodian and Anatolian fallow deer (Dama dama dama L., 1758)

The European fallow deer ( Dama dama dama ) is one of the most widespread cervids, and its distribution has been heavily affected by man. At present, only one wild autochthonous population is reputed to survive in Anatolia, but its census size is dramatically decreasing. This means that a significant portion of the ancestral genetic diversity of this taxon is seriously threatened. In the present study, a portion of the mitochondrial DNA (D-loop) in 37 D. d. dama specimens from three Mediterranean sites, Turkey, the island of Rhodes (Greece), and the Italian Peninsula, and seven individuals of the Persian fallow deer, Dama dama mesopotamica , was sequenced, and the results from the data analysis are interpreted in light of current archaeozoological and biogeographical knowledge. We conclude that: (1) D. d. mesopotamica is strongly differentiated from D. d. dama , confirming the results of previous genetic studies and (2) the Rhodian populations of D. d. dama , founded by humans in Neolithic times, possess a set of mitochondrial lineages, found in no other study populations. The persistence of these haplotypes is particularly significant because human-mediated processes (e.g. domestication) usually result in genetic depletion and erosion of an ancestral genetic pool. In the case of the Rhodes' population of fallow deer, we hypothesize that, during the foundation of this population, humans unknowingly preserved a remarkable portion of the original genetic diversity of the source population(s).  © 2008 The Linnean Society of London, Biological Journal of the Linnean Society , 2008, 93 , 835–844.     

The fossil record and estimating divergence times between lineages: Maximum divergene times and the importance of reliable phylogenies

Summary Bounded estimates on divergence times between lineaes are crucial to the calculation of absolute rates of molecular evolution. Upper (minimum) bounds on divergence times are easily estimated based on earliest fossil finds. Lower (maximum) bounds are more difficult to estimate; the age of putative ancestors may be used, though in practice it is virtually impossible to distinguish ancestors from primitive sister groups, which do not, of logical necessit, consitute lower bounds on divergence times. Two relatively new approaches to estimating lower bounds directly assess the incompleteness of the fossil record. The first uses taphonomic control groups to distinguish real absences from nonpreservation, while the second, and probably more powerful, uses the quality of the fossil recored to estimate confidence intervals on the bases of stratigraphic ranges. For some groups, especially vertebrates, the inclusion or exclusion of problematic fossils can dramaticaly affect estimated lower bounds on divergence times, often swamping the uncertainties due to the incompleteness of the fossil record and/or corelation and dating errors. When datable paleogeographic events reflect ancient divisions of faunas, a lower bound on the divergence time of speices within a fauna can be established based on the geologic, rather than fossil, record. The fossil records of hominids, eutherianmammals, echinoids, and geese are used as examples.This article was presented at the C.S.E.O.L. Conferrence on DNA-DNA Hybridization and Evolution, Lake Arrowhead, California, May 11–14, 1989     

Impact of long‐term chromosomal shuffling on the multispecies coalescent analysis of two anthropoid primate lineages

Multispecies coalescent (MSC) theory assumes that gene trees inferred from individual loci are independent trials of the MSC process. As genes might be physically close in syntenic associations spanning along chromosome regions, these assumptions might be flawed in evolutionary lineages with substantial karyotypic shuffling. Neotropical primates (NP) represent an ideal case for assessing the performance of MSC methods in such scenarios because chromosome diploid number varies significantly in this lineage. To this end, we investigated the effect of sequence length on the theoretical expectations of MSC model, as well as the results of coalescent‐based tree inference methods. This was carried out by comparing NP with hominids, a lineage in which chromosome macrostructure has been stable for at least 15 million years. We found that departure from the MSC model in Neotropical primates decreased with smaller sequence fragments, where sites sharing the same evolutionary history were more frequently found than in longer fragments. This scenario probably resulted from extensive karyotypic rearrangement occurring during the radiation of NP, contrary to the comparatively stable chromosome evolution in hominids.     

Localized hybridization betweenSaxifraga aizoides andS. mutata (Saxifragaceae): Reproductive ecology ofS. ×hausmannii and implications for conservation

The roles of hybridization and of introgression as potential threats to small native populations are current topics of interest both for evolutionary and conservation biologists. Two factors are mainly involved in the threat to natural populations through hybridization: demographic swamping and genetic assimilation. At prealpine locations, twoSaxifraga species with very different growth habits,S. aizoides andS. mutata, form a hybrid,S. ×hausmannii. Investigation of meiosis and crossing experiments revealed regular pairing of the 26 chromosomes and development of viable seeds in the hybrid. Analysis of hybrid indices, GPI allozymes, germination experiments and seed sizes showed an intermediate position ofS. ×hausmannii between its parental species.Saxifraga aizoides andS. mutata were separated by only weak hybridization barriers. Introgression occurred mostly in direction ofS. aizoides, although to a small amount. There is no actual threat to small, prealpine populations ofS. aizoides andS. mutata through interspecific gene flow because hybridization is localized, resulting from different flowering phenologies of the parental species and from the narrow habitat requirements ofS. ×hausmannii, which are similar to those ofS. aizoides. The major threat to local, prealpine populations ofS. aizoides andS. mutata is the loss of landscape dynamics. Both species need open erosion slopes for successful recruitment.     

Solar irradiance as the proximate cue for flowering in a tropical moist forest

We compared flowering times predicted by six possible proximate cues involving seasonal changes in rainfall and irradiance and flowering times observed over 30 years of weekly censuses for 19 tree and liana species from Barro Colorado Island (BCI), Panama. Hypotheses concerning variation in the timing and intensity of rainfall failed to predict flowering times in any species. In contrast, 10 to 12 weeks of consistent high levels of irradiance predicted flowering times well for eight species, and six or seven weeks of rapidly increasing levels of irradiance predicted flowering times well for two species. None of the six possible proximate cues predicted flowering times adequately for the nine remaining species. We conclude that high and increasing levels of irradiance are the proximate cues for flowering in many BCI species. The seasonal movements of the Intertropical Convergence Zone cause strong seasonal changes in cloud cover, atmospheric transmissivity, and irradiance reaching the BCI forest. Inter‐annual variation in the timing of movements of the Intertropical Convergence Zone is the most likely cause of inter‐annual variation in the timing of flowering in these species. Much work remains to be done as the physiological mechanisms linking flowering and irradiance are unknown and the proximate cues for flowering remain to be identified for many other BCI species.