An exploration of how to define and measure the evolution of behavior, learning, memory and mind across the full phylogenetic tree of life.

There are probably few terms in evolutionary studies regarding neuroscience issues that are used more frequently than 'behavior', 'learning', 'memory', and 'mind'. Yet there are probably as many different meanings of these terms as there are users of them. Further, investigators in such studies, while recognizing the full phylogenetic spectrum of life and the evolution of these phenomena, rarely go beyond mammals and other vertebrates in their investigations; invertebrates are sometimes included. What is rarely taken into consideration, though, is that to fully understand the evolution and significance for survival of these phenomena across phylogeny, it is essential that they be measured and compared in the same units of measurement across the full phylogenetic spectrum from aneural bacteria and protozoa to humans. This paper explores how these terms are generally used as well as how they might be operationally defined and measured to facilitate uniform examination and comparisons across the full phylogenetic spectrum of life. This paper has 2 goals: (1) to provide models for measuring the evolution of 'behavior' and its changes across the full phylogenetic spectrum, and (2) to explain why 'mind phenomena' cannot be measured scientifically at the present time.

Targeting host store-operated Ca(2+) release to attenuate viral infections.

Viruses coopt host intracellular Ca(2+) signaling pathways to optimize timing and effectiveness of infection stages against barriers to invasion, pathogenesis, replication, and release. Virus-induced changes in free cytosolic Ca(2+) levels facilitate virus adsorption, uncoating, catalysis, toxin production, structural assembly and stabilization, trafficking, and fusion and budding. Ca(2+)-associated alterations in virus status also selectively precipitate host cytopathologies through, among other events, retardation or induction of apoptosis, elevation of metabolic stress and reactive oxygen species production, and promotion of proinflammatory cytokine and chemokine synthesis and release. Viral particles and proteins tune spatiotemporal dynamics of host free cytosolic Ca(2+) concentrations by modulating Ca(2+) entry from the extracellular environment, upstream first or second messengers, ion- and ATP-dependent Ca2+ pumps that sequester or extrude free cytosolic Ca(2+), store-operated Ca(2+) mobilization and leakage, and viral capsid/envelope and downstream host Ca(2+) binding proteins and sensors. Each of these major viral mechanisms, briefly reviewed in this article, presents a suitable drug target capable of mitigating the severity and incidence of viral infections. Given its pivotal role in cellular response regulation, bioenergetics, posttranslational protein and lipid modification and transport, homeostasis, cell motility and morphogenesis, and T lymphocyte proliferation, targeting virally stimulated inositol 1,4,5-trisphoshate (IP3)-mediated store-operated Ca(2+) release especially offers unique, predictable benefits for augmenting immunoprotection in vertebrate clinical populations. We appraise possibilities of modulating this system with experimental proteins that gate activation kinetics of endoplasmic-reticulum-localized Ca(2+)-conducting IP3 receptors via allosteric protein-protein interactions. Such compounds are expected to be valuable in treating primary disease symptoms and sequelae, including virus-associated dementia.

A behavioral homeostasis theory of habituation and sensitization: II. Further developments and predictions.

Habituation may be viewed as a decremental behavioral change to iterative stimuli of little immediate relevance. It is observed from protozoa to humans, indicating its evolutionary significance. If habituation is interpreted as the process of filtering out unimportant repetitive stimuli, then how should sensitization be interpreted? The 'behavioral homeostasis theory' of these two behaviors is based on the notion that organisms at a high level of 'alertness' prior to experiencing a new iterative stimulus will show a large initial response followed by a decrement (habituation) if the stimulus is of little significance. Conversely, the same organism at a low level of 'alertness' will show a small initial response to the same stimulus followed by an increase in 'alertness' and a larger response to the next stimulus (sensitization) in order to receive enough information to assess its significance. Circadian rhythmicity is hypothesized to play a role in determining 'alertness' to a new iterative stimulus at any given time. The level of responsiveness in initial habituaters and sensitizers, as an asymptote is approached, is a balance between being too 'alert' to an unimportant stimulus and missing other significant stimuli, and being too 'un-alert' and missing a change in the relevance of the present iterative stimulus. The concept of 'behavioral homeostasis' includes behaviors beyond habituation and sensitization across phylogeny. It includes instinctive as well as learned, and group as well as individual behavior. Such behavioral homeostatic processes to optimize detection and assessment of constantly occurring external stimuli are critical for organism survival. Clinical implications of this theory are also examined.

Acute rheumatic fever associated with Henoch-Schönlein purpura: report of three cases and review of the literature.

AIM: To describe a possible relationship between Henoch-Schönlein purpura and rheumatic fever. METHODS: Patients with features of both diseases were identified by reviewing the hospital records. Medline and reference lists from published articles were used to search for previous reports of the two conditions occuring simultaneously. RESULTS: Three newly described cases, and three previous reports of Henoch-Schönlein purpura associated with rheumatic carditis or chorea were identified. CONCLUSIONS: The coexistence of these two disorders in some patients supports the view that Group A streptococcus may have a pathogenic role in Henoch-Schönlein purpura.

Transfer of learned information between ganglia in the insect ventral nerve cord.

A yoked control training procedure was used on the decapitated cockroach, L. maderae. The right prothoracic leg was trained to lift in order to avoid a shock. It was found that this information transferred via the two interganglionic connectives from the first or prothoracic ganglion (T1) to the second or mesothoracic ganglion (T2) so that now the right mesothoracic leg lifted to avoid shock even though it was not directly trained. If both connectives were cut before training T1, no transfer to T2 was seen, i.e. the mesothoracic leg did not lift and avoid shock. However, if both connectives were cut immediately after training T1, the information had already transferred and was available for use by T2. There was redundancy in the transfer in that either connective alone could carry the same information from T1 to T2. Either mesothoracic leg could tap into this information. Using a reversible cold block on the connectives, it was found that if it was applied before training T1 it did not interfere with T1 learning but no transfer to T2 was seen after the cold block wore off. That the block was transitory and did not permanently impair the connectives was shown by the fact that if it was applied and then allowed to wear off before training began there was normal learning in T1 and transfer to T2. The transection and cold-block studies were consistent in demonstrating that the transfer of the information was 'on-line' and only occurred during T1 learning. If transfer was blocked during T1 learning the information could not be transferred or tapped into by T2 at a later time even though it was stored in T1 and available for later use by T1. The transfer occurred so quickly it most likely occurred via nerve impulses. Because no primary sensory or motor neurons are in the connectives, the information must have been coded onto interneurones for transfer from the first (T1) to the second (T2) ganglion.

A ganglionic model of "learned helplessness".

The phenomenon known as "learned helplessness" (LH) is seen broadly across the animal kingdom. Some of the basic characteristics of this behavior are: failure to escape shock when it is possible to do so following non-escapable shock; reversion to non-escape behavior even after successful escape; if the animal is given escape/avoidance training prior to being given inescapable shocks, the latter will not interfere with its ability to later show normal escape/avoidance behavior (generally described as an immunization effect); following inescapable shock training the animals often become "passive and still" when confronted with an inescapable shock. These behaviors are seen in intact mammals, lower vertebrates, and invertebrates. In fact, the basic characteristics are even seen in a spinal rat and, with the exception of one characteristic not yet examined, in an isolated thoracic ganglion of an insect. The brain is evidently not essential either in mammals or in invertebrates for demonstrating this behavior. Not only can an insect ganglion show the behavioral characteristics of LH, but the neural information underlying the phenomenon of LH can be shown to transfer from one ganglion innervating one pair of legs to another ganglion innervating a different pair of legs. Thus, how CNS information underlying LH is coded and transferred from one site to another within the CNS can be examined in such a system. The LH model has provided valuable insights into the physiology of depression. This model suggests that human depression is caused by one's lack of control over traumatic events. It is supported by a number of parallels between depression and LH behavior. Tricyclic antidepressants, MAO inhibitors, and ECT, which are effective in treating depression, also can prevent and reverse LH in mammals. It would be important to find out if they are also effective in invertebrate models. The fact that the characteristics of the behavior called LH are seen in invertebrates such as slugs, cockroaches, and locusts provokes other intriguing questions about the presence of cognition at these phylogenetic levels, as well as what animal or preparation constitutes an appropriate model for human depression.

A comparative approach to the behavior called "learned helplessness'.

The phenomenon of 'learned helplessness' is seen broadly across the animal kingdom. The basic characteristics of this behavior are similar in intact mammals, lower vertebrates and invertebrates. In fact, the basic characteristics even are seen in an isolated thoracic ganglion of an insect. The brain is evidently not essential either in mammals or in invertebrates for demonstrating this behavior. A neutral terminology is suggested that allows for investigation of this behavior and its underlying mechanisms in both intact and surgically simplified preparations of both vertebrates and invertebrates. Thus, its phylogeny can be investigated. In addition, simpler systems such as the insect ventral nerve cord with its large neurons and its ease of pharmacological manipulation may have important contributions to make to understanding the neuropharmacology underlying it. The ubiquity of the phenomenon in different phyla suggests that while in the laboratory it may appear maladaptive, this may not necessarily be the case in a natural ecological context. Because of increasing governmental regulations in both Europe and the US on mammalian studies involving shock and distress, such as that associated with 'learned helplessness', it may be prudent to consider other systems that may offer insight into its underlying mechanisms.

Selecting a model system for neurobiological studies of learning and memory.

This article discusses the logic underlying the use of invertebrate model systems for investigating the neurobiological basis of learning and memory, the kinds of questions which can be asked of these systems as well as their limitations. A model system selected to answer specific questions about learning and memory is most useful if its selection is based on strategy rather than chance.

Magnetic resonance imaging (MRI) detection of the murine brain response to light: temporal differentiation and negative functional MRI changes.

Using a 9.4 T MRI instrument, we have obtained images of the mouse brain response to photic stimulation during a period between deep anesthesia and the early stages of arousal. The large image enhancements we observe (often >30%) are consistent with literature results extrapolated to 9.4 T. However, there are also two unusual aspects to our findings. (i) The visual area of the brain responds only to changes in stimulus intensity, suggesting that we directly detect operations of the M visual system pathway. Such a channel has been observed in mice by invasive electrophysiology, and described in detail for primates. (ii) Along with the typical positive response in the area of the occipital portion of the brain containing the visual cortex, another area displays decreased signal intensity upon stimulation.

Habituation of the galvanic skin response to tone as a function of age.

Habituation of the galvanic skin response (GSR) to tone in male college students varying in age from 18-39 years old was examined. Older subjects habituated more slowly to tone than did younger ones. This confirmed our past work on habituation of the GSR to electric shock. The GSR is shown to be a sensitive and reliable measure of small differences in age as it affects learning. The clinical usefulness of this quantitative and sensitive measure in detecting small and early changes in learning and memory deficits associated with age and dementia is discussed.

A unique syndrome of immunodeficiency and autoimmunity associated with absent T cell CD2 expression.

CD2 is a glycoprotein expressed on the surface of human T cells that mediates adhesion between T cells and antigen presenting cells. CD2 also functions in concert with the T cell receptor to transduce signals that lead to T cell activation. The CD8 and CD4 molecules are transmembrane glycoproteins that are expressed on mutually exclusive populations of mature T cells and bind to determinants on major histocompatibility complex class I and class II molecules respectively. Like CD2, CD4 and CD8 function to promote adhesion between T cells and antigen presenting cells and potentiate signaling via the T cell receptor. We studied a patient with idiopathic lymphopenia and disseminated infection with Mycobacterium avium. The patient also suffered from recurrent deep venous thrombosis in association with anticardiolipin and anti-DNA antibodies. Peripheral blood T cells from this patient were polyclonal and expressed no detectable CD2 RNA or protein as determined by northern blotting, immunofluorescent staining with anti-CD2 antibodies, and failure to form rosettes with sheep red blood cells. In addition, the majority (85%) of this patient's T cells did not express either CD4 or CD8 but did express the alpha/beta T cell receptor. T cells from this patient failed to respond to stimulation with alloantigen or specific antigen. In contrast, there was a normal response to stimulation with immobilized anti-CD3 antibody. The clinical and immunologic findings in this patient provide in vivo evidence that the accessory molecules CD2, CD4, and CD8 play important roles in the regulation of normal human T cell activation.

Leg position learning in the cockroach nerve cord using an analog technique.

The ultimate goal of this research is to correlate neural activity with leg behavior during learning. Contrary to previous studies of shock avoidance learning in the headless cockroach, in which an all-or-none method of recording was used, we have adopted a direct analog recording of leg position to measure learning in the prothoracic ganglion. This method provides a sensitive and continuous record of leg movement that can be correlated with the interactions of individual neurons that may be involved in such learning. Of the 10 prothoracic legs trained to flex to avoid shock, eight escaped shock by flexion within a maximum of 13 min and seven showed savings when retested. Only four of eight prothoracic legs trained to extend showed avoidance learning and all four showed savings. Electrical stimulation of nerves 3,4,5, and 6 innervating the prothoracic leg revealed which nerves were instrumental in the flexion and extension responses.

Common variable immunodeficiency: diagnosis and management.

OBJECTIVE: Common variable immunodeficiency is a heterogeneous syndrome characterized by humoral immunodeficiency, recurrent bacterial infections, and a variety of immunologic abnormalities. The goal of this article is to review the pathogenesis, clinical manifestations, diagnosis, and management of common variable immunodeficiency. DATA SOURCES: References are limited to the English language literature. Sources include computerized databases and bibliographies of recent articles and books. STUDY SELECTION: References that made important contributions to our understanding of the pathogenesis, clinical manifestations, diagnosis, and treatment of this disease were selected for inclusion in this review. RESULTS AND CONCLUSION: Common variable immunodeficiency is an idiopathic state of immune dysregulation that results in impaired antibody synthesis and the development of recurrent bacterial infections. This syndrome is also associated with a variety of autoimmune and neoplastic disorders. Effective management of these patients includes intravenous immunoglobulin replacement, vigorous treatment of infections, and readiness to promptly evaluate and treat unusual autoimmune and neoplastic complications should they appear.

B cell differentiation defects in common variable immunodeficiency are ameliorated after stimulation with anti-CD40 antibody and IL-10.

In these studies we show that although purified B cells of patients with common variable immunodeficiency (CVI) have a normal capacity to proliferate, they manifest differentiation defects at multiple levels. Compared with controls, circulating CVI B cell populations contain reduced numbers of sIgG+ and sIgA+ cells with a commensurate increase in sIgM+ B cells, suggesting an in vivo defect in isotype switch. In addition, CVI B cells manifest Ig secretion defects on stimulation with either anti-CD40 and IL-10 or SAC and IL-2 and IL-10, which are of increasing severity for IgM, IgG, and IgA, respectively. These Ig secretion defects are not overcome by addition of a variety of cytokines, including TGF-beta, to anti-CD40-driven cultures. In further studies we show that despite the above abnormalities, CVI B cells are induced to express normal or near-normal levels of C mu, C gamma, and C alpha mRNA after 7 days of stimulation with anti-CD40 and IL-10. That this CH mRNA expression represents a recovery of CVI B cell differentiation is supported by studies of Ig secretion in which CVI B cells that are first stimulated for 7 days with anti-CD40 and IL-10 and then restimulated in coculture with activated normal allogeneic T cells and IL-10, secrete substantial levels of IgM and IgG and increased amounts of IgA. Overall, therefore, CVI B cell function can be significantly improved by maintenance in culture. These data suggest the abnormalities of B cell differentiation in CVI are reversible and that the defect is a form of B cell anergy.

Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. A preliminary report.

BACKGROUND: Studies conducted in vitro and in animals suggest that cytokine signals to monocytes or macrophages by interferon gamma are important in the containment and clearance of disseminated nontuberculous mycobacterial infections. METHODS: We studied seven patients with refractory, disseminated nontuberculous mycobacterial infections who were not infected with the human immunodeficiency virus. Three patients were from a family predisposed to the development of Mycobacterium avium complex infections; four patients had idiopathic CD4+ T-lymphocytopenia. Their infections were culture- or biopsy-proved, involved at least two organ systems, and had been treated with the maximal tolerated medical therapy. Cellular proliferation, cytokine production, and phagocyte function were assessed in peripheral-blood cells. Interferon gamma was administered subcutaneously two or three times weekly in a dose of 25 to 50 micrograms per square meter of body-surface area in addition to antimycobacterial medications. Clinical effects were monitored by cultures, biopsies, radiographs, and in one patient a change in the need for paracentesis. RESULTS: In response to phytohemagglutinin, the production of interferon gamma by mononuclear cells from the patients was lower than in normal subjects (P < 0.001), whereas stimulation with ionomycin and phorbol myristate acetate led to normal production of interferon gamma in the patients. Within eight weeks of the start of interferon gamma therapy, all seven patients had marked clinical improvement, with abatement of fever, clearing of many lesions and quiescence of others, radiographic improvement, and a reduction in the need for paracentesis. CONCLUSIONS: Interferon gamma in combination with conventional therapy may be effective for some cases of refractory disseminated nontuberculous mycobacterial infection.