Intact Mammals Research Articles

In Silico Prediction of ADMET/Drug-likeness Properties of Bioactive Phloroglucinols from Hypericum genus.

Dimeric acylphloroglucinols occurring in species from sections Brathys and Trigynobrathys of the genus Hypericum exhibit acylfilicinic acid and acylphloroglucinol moieties linked by a methylene bridge. However, this chemical feature differs from hyperforin, from H. perforatum (Hypericum section), some dimeric acylphloroglucinols, such as uliginosin B, display similar pharmacological activities, namely antidepressant and antinociceptive. However, there is no knowledge about the pharmacokinetic profile and no toxicity studies of these compounds in intact mammals. to perform an in silico evaluation of the similarity, pharmacokinetics and toxicity (ADMET) properties of dimeric acylphloroglucinols from species native to Central and South America. ADMET prediction of eleven elected phloroglucinols followed by the chemical space evaluation of thirty-five dimeric acylphloroglucinols derivatives labeled according to their prenylation/geranylation pattern through principal component analysis (PCA). The similarity analysis was performed using the Tanimoto similarity index. ADMET properties were predicted with the open-source software SwissADME and pkCSM-pharmacokinetics. Several compounds showed good human intestinal absorption. However, they may present difficulties in crossing the blood-brain barrier, probably due to the high tPSA values. The predicted toxicity parameters indicated that most compounds have low toxicity. Most non-prenylated phloroglucinols were disposed into Lipinski's rule limits. Uliginosin B, isouliginosin B and japonica seem to be druglike compounds. The PCA model explained 77.49% of the total variance, and molecular similarity analyses revealed some expected similarities between isomers and different compounds. dimeric acylphloroglucinols may be promising drug candidates and deserve further pharmacological and medicinal chemistry studies.

Integrated evaluation of lung disease in single animals.

During infectious disease, pathogen load drives inflammation and immune response that together contribute to tissue injury often resulting in organ dysfunction. Pulmonary failure in SARS-CoV2-infected hospitalized COVID-19 patients is one such prominent example. Intervention strategies require characterization of the host-pathogen interaction by accurately assessing all of the above-mentioned disease parameters. To study infection in intact mammals, mice are often used as essential genetic models. Due to humane concerns, there is a constant unmet demand to develop studies that reduce the number of mice utilized while generating objective data. Here, we describe an integrated method of evaluating lung inflammation in mice infected with Pseudomonas aeruginosa or murine gammaherpesvirus (MHV)-68. This method conserves animal resources while permitting evaluation of disease mechanisms in both infection settings. Lungs from a single euthanized mouse were used for two purposes-biological assays to determine inflammation and infection load, as well as histology to evaluate tissue architecture. For this concurrent assessment of multiple parameters from a single euthanized mouse, we limit in-situ formalin fixation to the right lung of the cadaver. The unfixed left lung is collected immediately and divided into several segments for biological assays including determination of pathogen titer, assessment of infection-driven cytokine levels and appearance of cell death markers. In situ fixed right lung was then processed for histological determination of tissue injury and confirmation of infection-driven cell death patterns. This method reduces overall animal use and minimizes inter-animal variability that results from sacrificing different animals for different types of assays. The technique can be applied to any lung disease study in mice or other mammals.

Quantitative flux analysis in mammals.

Altered metabolic activity contributes to the pathogenesis of a number of diseases, including diabetes, heart failure, cancer, fibrosis and neurodegeneration. These diseases, and organismal metabolism more generally, are only partially recapitulated by cell culture models. Accordingly, it is important to measure metabolism in vivo. Over the past century, researchers studying glucose homeostasis have developed strategies for the measurement of tissue-specific and whole-body metabolic activity (pathway fluxes). The power of these strategies has been augmented by recent advances in metabolomics technologies. Here, we review techniques for measuring metabolic fluxes in intact mammals and discuss how to analyse and interpret the results. In tandem, we describe important findings from these techniques, and suggest promising avenues for their future application. Given the broad importance of metabolism to health and disease, more widespread application of these methods holds the potential to accelerate biomedical progress.

A low-cost, high-efficiency LED probe compatible with optical fiber port for optogenetics

Optogenetics, combining optical techniques with genetics study and aiming at probing the neural circuits of intact mammals and other animals, has rapidly become an essential technique in neuroscience. Typically, the awake behaving optogenetics experiments are conducted either by inserting into the brain a remote-laser-tethered optical fiber or by implanting a light emitting diode (LED) that connects to a remote power source wirelessly. However, the tethered fiber presents several problems, such as the mice biting the optical fiber and restricting the range of mice movement. The implanted LED solutions successfully solve these problems by moving the source of light close to the brain and implanting an LED mounted on a flexible substrate into the brain. Nevertheless, the tethered optical fiber system is still used as a universal method for its strong output power and long working time that cannot be replaced. But due to the variable implanted LED setups, optogenetics experiments are hard to be conducted, because the different implanted setups cost a lot of efforts and resources to adapt to the different interfaces. Here we developed a miniature, low-cost, high-efficiency, and modular LED probe to solve this problem, which is compatible with the optical fiber port, as a universal interface in optogenetics experiments.

Aminophylline increases parasternal muscle action in awake canines

The traditional theophylline bronchodilator, aminophylline, is still widely used, especially in the treatment of COPD. The effects of aminophylline on ventilation and action of the costal diaphragm have been previously defined, but other respiratory muscles – notably the chest wall, are not well determined. Therefore, we investigated the effects of aminophylline on the Parasternal intercostal, a key obligatory inspiratory muscle, examining muscle length, shortening and EMG. We studied 11 awake canines, chronically implanted with sonomicrometer crystals and fine-wire EMG electrodes in the parasternal muscle. Ventilatory parameters, muscle length (shortening), and moving average muscle EMG activity, were measured at baseline and with aminophylline, during resting and hypercapnic stimulated breathing. Experiments were carried out prior to administration of aminophylline (baseline), and 1.5 h after loading and ongoing infusion. Minute ventilation, tidal volume and respiratory frequency all increased significantly with aminophylline, both during resting breathing and at equivalent levels of hypercapnic stimulated breathing. Parasternal baseline muscle length was entirely unchanged with aminophylline. Parasternal shortening increased significantly with aminophylline while corresponding parasternal EMG activity remained constant, consistent with increased contractility. Thus, in awake, intact mammals, aminophylline, in the usual therapeutic range, elicits increased ventilation and increased contractility of all primary inspiratory respiratory muscles, including both chest wall and diaphragm.

Rat hippocampal responses up to 90 days after a single nanoceria dose extends a hierarchical oxidative stress model for nanoparticle toxicity

Ceria engineered nanomaterials (ENMs) have very promising commercial and therapeutic applications. Few reports address the effects of nanoceria in intact mammals, let alone long term exposure. This knowledge is essential to understand potential therapeutic applications of nanoceria in relation to its hazard assessment. The current study elucidates oxidative stress responses in the rat hippocampus 1 and 20 h, and 1, 7, 30 and 90 days following a single systemic infusion of 30 nm nanoceria. The results are incorporated into a previously described hierarchical oxidative stress (HOS) model. During the 1–20 h period, increases of the GSSG: GSH ratio and cytoprotective phase-II antioxidants were observed. During the 1–7 d period, cytoprotective phase-II antioxidants activities were inhibited with concomitant elevation of protein carbonyl (PC), 3-nitrotyrosine (3NT), heme oxygenase-1 (HO-1), cytokine IL-1β and the autophagy marker LC-3AB. At 30 day post ceria infusion, oxidative stress had its major impact. Phase-II enzyme activities were inhibited; concurrently PC, 3NT, HO-1 and Hsp70 levels were elevated along with augmentation of IL-1β, pro-apoptotic pro-caspase-3 and LC-3AB levels. This progress of escalating oxidative stress was reversed at 90 days when phase-II enzyme levels and activities were restored to normal levels, PC and 3NT levels were reduced to baseline, cytokine and pro-caspase-3 levels were suppressed, and cellular redox balance was restored in the rat hippocampus. This study demonstrates that a single administration of nanoceria induced oxidative stress that escalates to 30 days then terminates, in spite of the previously reported continued presence of nanoceria in peripheral organs. These results for the first time confirm in vivo the HOS model of response to ENM previously posited based on in vitro studies and extends this prior hierarchical oxidative stress model that described three tiers to a 4th tier, characterized by resolution of the oxidative stress and return to normal conditions.

Effect of Intracerebroventricular Injection of TiO<SUB>2</SUB> Nanoparticles on Complex Behaviour in the Rat

There are no data available on the behavioural effects of centrally administered nanoparticles in freely moving intact mammals. Consequently, in the current study male Sprague-Dawley rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement. Under this schedule, ascending and descending sequences of fixed-ratio (FR) lever press requirements for food reinforcement were presented over six cycles, with each discrete FR component completed on the alternate lever to the previous component. The final version of the schedule was comprised of an ascending followed by a descending sequence of the ratio values 2, 6, 12, 20, 30, 42 and 56, repeated over six cycles. When the rats were able to complete this version of the ALCR schedule in 40 min, each was implanted with a permanently indwelling ICV cannula aimed at the lateral ventricle of the brain, and allowed to recover for 7 days. On the first day of the experiment, all rats were injected with either titanium dioxide (TiO2, 9 nm, stabilised with gallic acid, 10 microl volume, 2 mg/ml) nanoparticles, or 10 microl saline (control). Two-hours after the ICV injections, the behaviour of all rats was measured using the ALCR schedule, and their behaviour was also measured (no ICV injection) for the next 7 days. Under the ALCR schedule, the number of lever-switching errors and incorrect lever perseverations significantly increased in the TiO2 group (p < 0.05). Other parameters of the ALCR schedule (RRRs and PRPs), which indicate the induction of malaise or general motor retardation, were not altered following ICV TiO2 injection. The findings of the current study indicate that central administration of TiO2 nanoparticles induced behavioural deterioration in freely moving intact animals, that the induced behavioural deterioration was a result of central rather than peripheral outcomes, and that this effect was chronic rather than acute.

Imaging of superoxide generation in the dopaminergic area of the brain in Parkinson's disease, using mito-TEMPO.

We report a new methodology for direct visualization of superoxide production in the dopaminergic area of the brain in Parkinson's disease, based on the redox cycle of mito-TEMPO, a blood-brain barrier-, cell-, and mitochondria-penetrating nitroxide derivative with superoxide scavenging properties and T1 magnetic resonance imaging (MRI) contrast. The experiments were conducted on healthy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. In healthy mice, the nitroxide-enhanced MRI signal was weak and short-lived (half-life ∼ 40 s; duration ∼ 80 s). The profile of the histograms indicated a high reducing activity of normal brain tissues against mito-TEMPO. In MPTP-treated mice, the nitroxide-enhanced MRI signal was strong and long-lived (half-life > 20 min; duration > 20 min), especially in the dopaminergic area of the brain. The histograms indicated a high oxidative activity in dopaminergic tissues of MPTP-treated mice. The results show directly, on intact mammals, that superoxide is a major inducer and/or mediator of neurodegenerative damage in Parkinson's disease. The high oxidative status of brain tissue in Parkinson's disease was also confirmed on isolated tissue specimens, using total reducing capacity assay and ROS/RNS assay.

Role of Inhibition in Respiratory Pattern Generation

Postsynaptic inhibition is a key element of neural circuits underlying behavior, with 20-50% of all mammalian (nongranule) neurons considered inhibitory. For rhythmic movements in mammals, e.g., walking, swimming, suckling, chewing, and breathing, inhibition is often hypothesized to play an essential rhythmogenic role. Here we study the role of fast synaptic inhibitory neurotransmission in the generation of breathing pattern by blocking GABA(A) and glycine receptors in the preBötzinger complex (preBötC), a site essential for generation of normal breathing pattern, and in the neighboring Bötzinger complex (BötC). The breathing rhythm continued following this blockade, but the lung inflation-induced Breuer-Hering inspiratory inhibitory reflex was suppressed. The antagonists were efficacious, as this blockade abolished the profound effects of the exogenously applied GABA(A) receptor agonist muscimol or glycine, either of which under control conditions stopped breathing in vagus-intact or vagotomized, anesthetized, spontaneously breathing adult rats. In vagotomized rats, GABA(A)ergic and glycinergic antagonists had little, if any, effect on rhythm. The effect in vagus-intact rats was to slow the rhythm to a pace equivalent to that seen after suppression of the aforementioned Breuer-Hering inflation reflex. We conclude that postsynaptic inhibition within the preBötC and BötC is not essential for generation of normal respiratory rhythm in intact mammals. We suggest the primary role of inhibition is in shaping the pattern of respiratory motor output, assuring its stability, and in mediating reflex or volitional apnea, but not in the generation of rhythm per se.

Fungi and the rise of mammals.

Here are two indisputable facts: we are living in the age of mammals [1], and immunologically intact mammals are highly resistant to fungal diseases, such that most human systemic fungal are considered ‘‘opportunistic’’ [2]. Could these two facts be connected? The mammalian lifestyle is characterized by endothermy, homeothermy, and care for the young, including nourishment via lactation, all of which are energetically costly activities. In contrast, reptiles, which are ectotherms, require about one-tenth of the daily mammalian energy needs [3], and reptilian development is faster and requires less parental involvement. Given this energy handicap, how did mammals replace reptiles as the dominant land animals? This essay further develops the hypothesis originally proposed seven years ago that fungi contributed to the emergence of mammals by creating a fungal filter at the end of the Cretaceous that selected for the mammalian lifestyle and against reptiles [4].

Mammalian Endothermy Optimally Restricts Fungi and Metabolic Costs

Endothermy and homeothermy are mammalian characteristics whose evolutionary origins are poorly understood. Given that fungal species rapidly lose their capacity for growth above ambient temperatures, we have proposed that mammalian endothermy enhances fitness by creating exclusionary thermal zones that protect against fungal disease. According to this view, the relative paucity of invasive fungal diseases in immunologically intact mammals relative to other infectious diseases would reflect an inability of most fungal species to establish themselves in a mammalian host. In this study, that hypothesis was tested by modeling the fitness increase with temperature versus its metabolic costs. We analyzed the tradeoff involved between the costs of the excess metabolic rates required to maintain a body temperature and the benefit gained by creating a thermal exclusion zone that protects against environmental microbes such as fungi. The result yields an optimum at 36.7°C, which closely approximates mammalian body temperatures. This calculation is consistent with and supportive of the notion that an intrinsic thermally based resistance against fungal diseases could have contributed to the success of mammals in the Tertiary relative to that of other vertebrates.

Seeing Genes at Work in the Living Brain with Non-Invasive Molecular Imaging

Over the past ten years, a variety of imaging techniques have been developed that allow non-invasive detection of gene expression within the brain of intact mammals, ranging from mouse to man. The basic concepts of these imaging techniques, including positron emission tomography, single photon emission computed tomography, magnetic resonance imaging and spectroscopy, bioluminescence imaging and fluorescent imaging, are discussed. The expression of imaging reporter genes can be detected and quantified by these imaging techniques, which allow to unravel the temporospatial dynamics of gene expression within the intact living animal. Different imaging reporter genes have been developed each with their specific use in the basic and clinical neurosciences. Applications of reporter gene imaging can be found in neurooncology, infectious disease of the central nervous system, brain gene transfer, neural cellular therapy and in transgenic mice. Strategies that aim to image gene expression based on detection of mRNA levels have also been developed. We anticipate that these techniques will have a strong impact on preclinical neuroscience and will be of utmost importance in the implementation of gene and cell therapy for diseases of the brain.

Aminophylline increases ventilation and diaphragm contractility in awake canines

Traditional theophylline bronchodilators are still used clinically, especially in COPD. However, the effect of theophyllines on ventilation and respiratory muscles remains uncertain and these effects have not been measured directly in any awake, intact mammal. We hypothesized that aminophylline in the usual therapeutic dosage range, would elicit in the awake mammal, a significant increase in ventilation, and a significant increase in costal diaphragm shortening and contractility as recorded directly from the muscle. Therefore, we studied 13 awake canines, which had been chronically implanted with fine-wire EMG electrodes and sonomicrometer crystals in the costal segment of the diaphragm. Ventilatory parameters, moving average muscle EMG activity and muscle length and shortening, were measured at baseline and with aminophylline, during resting and hypercapnic stimulated breathing. Experiments were carried out prior to administration of aminophylline (baseline), and 1.5h after loading and ongoing infusion with aminophylline. Minute ventilation, tidal volume and respiratory frequency all increased significantly with aminophylline, both during resting breathing and at equivalent levels of hypercapnic stimulated breathing. Costal diaphragm baseline muscle length was entirely unchanged with aminophylline. Costal diaphragm shortening increased significantly with aminophylline while corresponding costal diaphragm EMG activity remained constant, consistent with increased diaphragm contractility. Thus, in awake, intact mammals, aminophylline in usual therapeutic dosage elicits increased ventilation and increased contractility of respiratory muscles.

In vivo mouse inferior olive neurons exhibit heterogeneous subthreshold oscillations and spiking patterns

In vitro whole-cell recordings of the inferior olive have demonstrated that its neurons are electrotonically coupled and have a tendency to oscillate. However, it remains to be shown to what extent subthreshold oscillations do indeed occur in the inferior olive in vivo and whether its spatiotemporal firing pattern may be dynamically generated by including or excluding different types of oscillatory neurons. Here, we did whole-cell recordings of olivary neurons in vivo to investigate the relation between their subthreshold activities and their spiking behavior in an intact brain. The vast majority of neurons (85%) showed subthreshold oscillatory activities. The frequencies of these subthreshold oscillations were used to distinguish four main olivary subtypes by statistical means. Type I showed both sinusoidal subthreshold oscillations (SSTOs) and low-threshold Ca(2+) oscillations (LTOs) (16%); type II showed only sinusoidal subthreshold oscillations (13%); type III showed only low-threshold Ca(2+) oscillations (56%); and type IV did not reveal any subthreshold oscillations (15%). These subthreshold oscillation frequencies were strongly correlated with the frequencies of preferred spiking. The frequency characteristics of the subthreshold oscillations and spiking behavior of virtually all olivary neurons were stable throughout the recordings. However, the occurrence of spontaneous or evoked action potentials modified the subthreshold oscillation by resetting the phase of its peak toward 90 degrees . Together, these findings indicate that the inferior olive in intact mammals offers a rich repertoire of different neurons with relatively stable frequency settings, which can be used to generate and reset temporal firing patterns in a dynamically coupled ensemble.

Novel Data Supporting the Two Respiratory Rhythm Oscillator Hypothesis. Focus on “Respiration-Related Rhythmic Activity in the Rostral Medulla of Newborn Rats”

Among the most rewarding moments in scientific discovery are when the pieces of a puzzle provided by different laboratories start to fall into place, forming a coherent and new view of the world. Several years ago, a consensus was emerging that respiratory rhythm in mammals arose from a single

Microwave Tomographic Imaging of the Heart in Intact Swine

Microwave tomography is a new imaging modality based on differentiation of tissue dielectric properties. The main objective of our research project is to develop a microwave tomographic approach for non-invasive assessment of functional viability of myocardial tissue, including detection of infarcted tissue. Imaging of the heart in intact, euthanized animals is the first step towards this objective. When microwave tomography is used to image the thorax of intact animals, it faces two major problems: — the structural complexity of the rib area with high reflection of electromagnetic (EM) radiation from its boundaries, and the potential for high reflection of EM radiation from the lung, filled with air. In addition, when a targeted object (a heart in our case) is located inside of a larger high scattered object (a torso), the level of EM field scattered by the internal object has to be technically detectable from the stronger EM field scattered by torso. The goal of this research study is to evaluate the degree of complexity of these problems, to understand some technical requirements for clinically applicable MWT system and to demonstrate the feasibility of microwave tomography for imaging of the heart in intact mammals using a swine model. Experiments were conducted on pigs (Yorkshire Domestic Cross/Farm Pigs) using a modified three-dimensional (3D) microwave tomographic (MWT) system operating at frequency 0.9 GHz. The presence of the heart in torso changes the amplitude of EM field by about 10–20% and changes the phase of EM field by about 7–10 degrees (mean absolute differences). Microwave tomographic images of swine torso and intact euthanized animals were obtained and discussed. Images reveal intra-torso and organ anatomy, including the heart and left ventricular chamber.

Fungal virulence, vertebrate endothermy, and dinosaur extinction: is there a connection?

Fungi are relatively rare causes of life-threatening systemic disease in immunologically intact mammals despite being frequent pathogens in insects, amphibians, and plants. Given that virulence is a complex trait, the capacity of certain soil fungi to infect, persist, and cause disease in animals despite no apparent requirement for animal hosts in replication or survival presents a paradox. In recent years studies with amoeba, slime molds, and worms have led to the proposal that interactions between fungi and other environmental microbes, including predators, select for characteristics that are also suitable for survival in animal hosts. Given that most fungal species grow best at ambient temperatures, the high body temperature of endothermic animals must provide a thermal barrier for protection against infection with a large number of fungi. Fungal disease is relatively common in birds but most are caused by only a few thermotolerant species. The relative resistance of endothermic vertebrates to fungal diseases is likely a result of higher body temperatures combined with immune defenses. Protection against fungal diseases could have been a powerful selective mechanism for endothermy in certain vertebrates. Deforestation and proliferation of fungal spores at cretaceous–tertiary boundary suggests that fungal diseases could have contributed to the demise of dinosaurs and the flourishing of mammalian species.

History of the science of mutagenesis from a personal perspective

A career in the study of mutagenesis spanning 50 years is a gift few scientists have been bestowed. My tenure in the field started in 1953, the year the structure of DNA became known (Watson and Crick [1953]: Nature 171:737). Before that time, it was suspected that DNA was the genetic material based on the research of Oswald T. Avery (Avery et al. [1944]: J Exp Med 79:137), but many scientists still believed that proteins or polysaccharides could be the genetic material. The present article describes a lifetime of personal experience in the field of chemical mutagenesis. The methods used to treat viruses with chemical mutagens were well developed in the 1950s. Here I review the early use of nitrous acid and hydroxylamine as mutagens in eukaryotes, the development of methods for the metabolic activation of mutagens by microsomal preparations, and the selection of a mutant tester set for the qualitative characterization of the mutagenic activity of chemicals. These studies provided critical background information that was used by Bruce Ames in the development of his Salmonella/microsome assay, widely known as the Ames test (Ames et al. [1973]: Proc Nat Acad Sci USA 70:2281-2285). This article also describes how a set of diagnostic chemical mutagens was selected and used to identify the molecular nature of gene mutations. Today, DNA sequencing has replaced the use of diagnostic mutagens, but studies of this kind formed the foundation of modern mutation research. They also helped set the stage for the organization of the Environmental Mutagen Society and the Environmental Mutagen Information Center, which are described. The article ends with the development of mammalian single-cell mutation assays, the first system for studying in vivo mutagenesis using recoverable vectors in transgenic animals, other mutation assays in intact mammals, and my thoughts on the critically important area of germ cell mutagenesis. This narrative is not a complete autobiographical account, in that I have selected only those experiences that I feel are important for the history of the field and the edification of today's students. I hope I have shown that science not only is a valuable pursuit but can also be fun, stimulating, and satisfying. A good sense of humor and the knowledge that many discoveries come by serendipity are essential.

Response of the respiratory network of mice to hyperthermia.

Most mammals modulate respiratory frequency (RF) to dissipate heat (i.e., panting) and avoid heat stroke during hyperthermic conditions. During hyperthermia, the RF of intact mammals increases and then declines or ceases (apnea). It has been proposed that this RF modulation depends on the presence of higher brain structures such as the hypothalamus. However, the direct effects of hyperthermia on the respiratory neural network have not been examined. To address this issue, the respiratory neural network [i.e., ventral respiratory group (VRG)] was isolated in a brain stem preparation taken from the medulla of mice (P0 -P6). Integrated population activity, predominated by inspiratory neurons, was recorded extracellularly from VRG neurons. The bath temperature was then heated from 30 to 40 degrees C, resulting in a biphasic frequency response in VRG activity. Following an initial six- to sevenfold increase and subsequent decline, fictive RF was maintained at a frequency that was higher than baseline frequency; at 40 degrees C, the RF was maintained at about two to four times that at 30 degrees C. The inspiratory burst amplitude and duration were significantly reduced during hyperthermic conditions. An increase in RF and decrease in VRG burst amplitude and duration also occurred when heating from 37 to 40 degrees C. Fictive apnea typically occurred during cooling to the control temperature. Furthermore, changes in hypoglossal motor nucleus activity paralleled those of the VRG, suggesting that temperature modulation of the VRG is likely to have a behaviorally relevant impact on respiration. We conclude that the VRG activity itself is modulated during hyperthermia and the respiratory network is particularly sensitive to temperature changes.

The evolutionary significance of habituation and sensitization across phylogeny: A behavioral homeostasis model

The phenomenon of habituation may be interpreted as a process that has evolved for filtering out iterative stimuli of little present relevance. That habituation is seen in aneural as well as neural organisms throughout phylogeny with remarkably similar characteristics suggests that its role is an important one in animal survival. If habituation is to be viewed as a process to filter out iterative stimuli that have no significant consequences, then how is sensitization to be viewed? One way of viewing these two behavioral changes, i.e. habituation and sensitization, is that they are homeostatic processes which optimize an organism’s likelihood of detecting and assessing the significance of a stimulus in a new iterative series or a change in it. If one views the level of initial responsiveness to a new stimulus as a function of an organism’s threshold just prior to stimulus occurrence, then “high responders” (i.e. those who initially react more strongly) are assumed to have a lower threshold for detecting and assessing the significance of this stimulus than are the “low responders” (i.e. those who initially react more weakly). Thus, high-responders would initially receive more sensory input and progressively decrease their responsiveness to a non-threatening stimulus (habituation). Likewise, initial low-responders would receive less sensory input followed by a decreased threshold and an increased response to the next stimulus occurrence (sensitization). The level of responsiveness achieved in both habituaters and sensitizers, as an asymptote is approached, is a balance between being too sensitive to an unimportant stimulus (and possibly missing other significant stimuli) and being too insensitive, and missing a change in the relevance of the present stimulus. These response changes can be taken as indices of the organism’s mechanisms for achieving an appropriate threshold level to an iterative stimulus in order to accurately assess its present significance and then eventually to asymptote at an optimal stable response level. This approach toward an asymptote is a behavioral homeostatic process that reflects the accumulated significance of the iterative stimulus at each occurrence. The purpose of adding “behavioral” to the term “homeostasis” is to extend the usual meaning of the concept from primarily internal processes to also include (a) iterative external stimulation, (b) the organism’s initial threshold to the initial stimulus as well as (c) the behavior which results from it. Since we are discussing organisms that range from intact, single-celled protozoa to intact mammals, as well as surgically simplified preparations, the termsstimulus, response andbehavior will be used broadly. While other investigators have focused on specific cellular mechanisms underlying habituation and sensitization in a given organism, this paper focuses on the adaptive significance of these two behavioral processes viewed across phylogeny.