Biomedical subjects

Russell D Fernald

Publications and source records attributed to Russell D Fernald.

At least 19 recordsLinked to original sources

PubMed2006

Social dominance regulates androgen and estrogen receptor gene expression.

In Astatotilapia burtoni, dominant males have higher levels of sex steroid hormones than subordinate males. Because of the complex regulatory interactions between steroid hormones and receptors, we asked whether dominance is also associated with variation in sex steroid receptor gene expression. Using quantitative PCR, we compared the expression of specific subtypes of androgen (AR) and estrogen (ER) receptor genes between dominant and subordinated males in 3 divisions of the brain, the pituitary, and the testes. We measured mRNA levels of AR-alpha, AR-beta, ER-alpha, ER-betaa, and ER-betab, gonadotropin-releasing hormone 1 (GnRH1), and GnRH receptor 1 (GnRH-R1) relative to 18S rRNA. In the anterior part of the brain, we found that dominant males had higher mRNA expression of AR-alpha, AR-beta, ER-betaa, and ER-betab, but not ER-alpha, compared to subordinate males. This effect of dominance was reflected in a positive correlation between testes size and AR-alpha, AR-beta, ER-betaa, and ER-betab in the anterior brain. In addition, mRNA levels of all ARs and ERs in the anterior brain were positively correlated with mRNA level of GnRH1. In the middle and posterior portions of the brain, as well as the testes, steroid receptor mRNA levels were similar among dominants and subordinates. In the pituitary, ER-alpha mRNA level was positively correlated with testes size and AR-alpha mRNA was positively correlated with GnRH-R1 mRNA level. These data suggest that dominant male brains could be more sensitive to sex steroids, which may contribute to the increased complexity of the behavioral repertoires of dominant males.

Animals↗

PubMed2006

Casting a genetic light on the evolution of eyes.

Light has been exploited for information by organisms through the evolution of photoreceptors and, ultimately, eyes in animals. Only a handful of eye types exist because the physics of light constrains photodetection. In the past few years, genetic tools have revealed several parallel pathways through which light guides behavior and have provided insights into the convergent evolution of eyes. The gene encoding opsin (the primary phototransduction protein) and some developmental genes had very early origins and were recruited repeatedly during eye evolution. Eye lens proteins arose separately and make up a diverse group, many of which were co-opted from other functions. A major challenge now is understanding how newly discovered pathways for processing light evolved and how they collaborate with eyes to harvest information from light.

Animals↗

PubMed2006

Remodeling of the cone photoreceptor mosaic during metamorphosis of flounder (Pseudopleuronectes americanus).

The retinal cone mosaic of the winter flounder, Pseudopleuronectes americanus, is extensively remodeled during metamorphosis when its visual system shifts from monochromatic to trichromatic. Here we describe the reorganization and re-specification of existing cone subtypes in which larval cones alter their spatial arrangement, morphology, and opsin expression to determine whether mechanisms controlling cell birth, mosaic position, and opsin selection are coordinated or independent. We labeled dividing cells with tritiated ((3)H) thymidine prior to mosaic remodeling to determine whether existing cone photoreceptors change phenotype. We also used in situ hybridization to identify mosaic type and opsin expression in transitional retinas to understand the sequence of transformation. Our data indicate that in the winter flounder retina the choice of new opsin species and the cellular rearrangement of the mosaic proceed independently. The production of the precise cone mosaic arrangement is not due to a stereotyped series of sequential cellular inductions, but rather might be the product of a set of distinct, flexible processes that rely on plasticity in cell phenotype.

Alkaline Phosphatase↗

PubMed2006

Chronic valproic acid treatment triggers increased neuropeptide y expression and signaling in rat nucleus reticularis thalami.

Valproate (VPA) can suppress absence and other seizures, but its precise mechanisms of action are not completely understood. We investigated whether VPA influences the expression of neuropeptide Y (NPY), an endogenous anticonvulsant. Chronic VPA administration to young rats (300-600 mg.kg(-1).d(-1) in divided doses over 4 d) resulted in a 30-50% increase in NPY mRNA and protein expression in the nucleus reticularis thalami (nRt) and hippocampus, but not in the neocortex, as shown by real-time PCR, radioimmunoassay, and immunohistochemistry. No increased expression was observed after a single acute dose of VPA. Chronic treatment with the pharmacologically inactive VPA analog octanoic acid did not elicit changes in NPY expression. No significant expression changes could be shown for the mRNAs of the Y1 receptor or of the neuropeptides somatostatin, vasoactive intestinal polypeptide, and choleocystokinin. Fewer synchronous spontaneous epileptiform oscillations were recorded in thalamic slices from VPA-treated animals, and oscillation duration as well as the period of spontaneous and evoked oscillations were decreased. Application of the Y1 receptor inhibitor N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-amide (BIBP3226) enhanced thalamic oscillations, indicating that NPY is released during those oscillations and acts to downregulate oscillatory strength. Chronic VPA treatment significantly potentiated the effect of BIBP3226 on oscillation duration but not on oscillation period. These results demonstrate a novel mechanism for the antiepileptic actions of chronic VPA therapy.

Action Potentials↗

PubMed2006

Differential social regulation of two pituitary gonadotropin-releasing hormone receptors.

In many vertebrates, social interactions regulate reproductive capacity by altering the activity of the hypothalamic-pituitary-gonadal (HPG) axis. To better understand the mechanisms underlying social regulation of reproduction, we investigated the relationship between social status and one main component of the HPG axis: expression levels of gonadotropin-releasing hormone receptor (GnRH-R). Social interactions dictate reproductive capacity in the cichlid fish Astatotilapia burtoni. Reproductively active territory holders suppress the HPG axis of non-territorial males through repeated aggressive encounters. To determine whether the expression of GnRH-R is socially regulated, we quantified mRNA levels of two GnRH-R variants in the pituitaries and brains of territorial (T) and non-territorial (NT) A. burtoni males. We found that T males had significantly higher levels of pituitary GnRH-R1 mRNA than NT males. In contrast, GnRH-R2 mRNA levels in the pituitary did not vary with social status. Pituitaries from both T and NT males expressed significantly higher mRNA levels of GnRH-R1 than GnRH-R2. GnRH mRNA levels in the brain correlated positively with GnRH-R1 mRNA levels in the pituitary but did not correlate with pituitary GnRH-R2. Measurements of GnRH-R1 and GnRH-R2 mRNA levels across the whole brain revealed no social status differences. These results show that, in addition to the known effects of social status on other levels of the HPG axis, GnRH receptor in the pituitary is also a target of social regulation.

Animals↗

PubMed2006

Distributions of two gonadotropin-releasing hormone receptor types in a cichlid fish suggest functional specialization.

Gonadotropin-releasing hormone 1 (GnRH1) from the brain controls reproduction in vertebrates via a GnRH-specific receptor in the pituitary; however, other forms of GnRH are found in all species, suggesting additional roles for this family of peptides. GnRH action depends critically on the location of its cognate receptors in the brain. To understand the potential roles of additional GnRH forms, we localized two known GnRH receptor types in a cichlid fish, Astatotilapia burtoni, in which GnRH1 is socially regulated. Using in situ hybridization, we describe the mRNA expression pattern of these GnRH receptor (GnRH-R) subtypes in the brain, specifically with respect to GnRH-producing neurons. Our data suggest that following a gene duplication, the two GnRH receptors have evolved to serve different functions. The type 1 receptor (GnRH-R1) is expressed less widely than the type 2 receptor (GnRH-R2). Specifically, GnRH-R1 is expressed in groups of neurons in the telencephalon, preoptic area, ventral hypothalamus, thalamus, and pituitary. In contrast, GnRH-R2 is expressed in many more brain areas, including the olfactory bulb, telencephalon, preoptic area, hypothalamus, thalamus, midbrain, optic tectum, cerebellum, hindbrain, and pituitary. The specific distribution of GnRH-R2 suggests that the GnRH ligands may act via this receptor to influence behavior in A. burtoni. Moreover, only GnRH-R2 mRNA is colocalized in the three known groups of GnRH-containing neurons, suggesting that any direct feedback regulation of GnRH by itself must act through this receptor type. Taken together, these data suggest that the two GnRH receptor types serve different functional roles in A. burtoni.

Animals↗

PubMed2006

Physiological consequences of social descent: studies in Astatotilapia burtoni.

In many species, social interactions regulate reproductive capacity, although the exact mechanisms of such regulation are unclear. Since social stress is often related to reproductive regulation, we measured the physiological signatures of change in reproductive state as they relate to short-term stress and the stress hormone cortisol. We used an African cichlid fish, Astatotilapia burtoni, with two distinct, reversible male phenotypes: dominant (territorial, T) males that are larger, more brightly colored, more aggressive, and reproductively competent and non-dominant males (non-territorial, NT) that are smaller, camouflage colored, and have regressed gonads. Male status, and hence reproductive competence, depends on social experience in this system. Specifically, if a T male is placed among larger male fish, it quickly becomes NT in behavior and coloration, but complete regression of its reproductive axis takes ca. 3 weeks (White et al. 2002). Reproduction in all vertebrates is controlled by the hypothalamic-pituitary-gonadal axis in which the key signaling molecule from the brain to the pituitary is GnRH1. Here, we subjected T males to territory loss, a social manipulation which results in status descent. We measured the effects of this status change in levels of circulating cortisol and testosterone as well as mRNA levels of GnRH1 and GnRH receptor-1 (GnRH-R1) in the brain and pituitary, respectively. Following short-term social suppression (4 h), no change was observed in plasma cortisol level, GnRH1 mRNA expression, GnRH-R1 mRNA expression, or plasma testosterone level. However, following a somewhat longer social suppression (24 h), cortisol and GnRH1 mRNA levels were significantly increased, and testosterone levels were significantly decreased. These results suggest that in the short run, deposed T males essentially mount a neural 'defense' against loss of status.

Animals↗

PubMed2005

Rapid behavioral and genomic responses to social opportunity.

From primates to bees, social status regulates reproduction. In the cichlid fish Astatotilapia (Haplochromis) burtoni, subordinate males have reduced fertility and must become dominant to reproduce. This increase in sexual capacity is orchestrated by neurons in the preoptic area, which enlarge in response to dominance and increase expression of gonadotropin-releasing hormone 1 (GnRH1), a peptide critical for reproduction. Using a novel behavioral paradigm, we show for the first time that subordinate males can become dominant within minutes of an opportunity to do so, displaying dramatic changes in body coloration and behavior. We also found that social opportunity induced expression of the immediate-early gene egr-1 in the anterior preoptic area, peaking in regions with high densities of GnRH1 neurons, and not in brain regions that express the related peptides GnRH2 and GnRH3. This genomic response did not occur in stable subordinate or stable dominant males even though stable dominants, like ascending males, displayed dominance behaviors. Moreover, egr-1 in the optic tectum and the cerebellum was similarly induced in all experimental groups, showing that egr-1 induction in the anterior preoptic area of ascending males was specific to this brain region. Because egr-1 codes for a transcription factor important in neural plasticity, induction of egr-1 in the anterior preoptic area by social opportunity could be an early trigger in the molecular cascade that culminates in enhanced fertility and other long-term physiological changes associated with dominance.

Animals↗

PubMed2005

Androgen level and male social status in the African cichlid, Astatotilapia burtoni.

In vertebrates, circulating androgen levels are regulated by the hypothalamic-pituitary-gonadal (HPG) axis through which the brain controls the gonads via the pituitary. Androgen levels ultimately depend on factors including season, temperature, social circumstance, age, and other variables related to reproductive capacity and opportunity. Previous studies with an African cichlid fish, Astatotilapia burtoni, suggested that changes in both testosterone and 11-ketotestosterone (11-KT), an androgen specific to teleost fish, depend on male social status. Here we characterize circulating plasma concentrations of testosterone and 11-KT in socially dominant (territorial) and socially subordinate (non-territorial) males. Territorial males have significantly higher circulating levels of both forms of androgen, which is another defining difference between dominant and subordinate males in this species. These results underscore how internal and external cues related to reproduction are integrated at the level of the HPG axis.

Animals↗

PubMed2005

Two visual processing pathways are targeted by gonadotropin-releasing hormone in the retina.

In fish the terminal nerve is comprised of a group of cells with somata adjacent to the olfactory bulb and processes that extend both anteriorly to the olfactory mucosa and posteriorly to the telencephalon. In teleost fish an additional group of axons extends along the optic tract and delivers putative neuromodulators to the retina. One peptide - gonadotropin-releasing hormone (GnRH) - has been implicated as a prime candidate neuromodulator based on electrophysiological evidence that exogenous application influences neural activity. Here we describe the expression patterns of two GnRH receptor subtypes in the retina of a teleost fish, Astatotilapia (Haplochromis) burtoni. The type 1 GnRH receptor (GnRH-R1) was expressed in cells of the amacrine cell layer - where lateral inputs affect the flow of visual information from photoreceptors to the brain - and in a distribution and location pattern similar to dopaminergic interplexiform cells. Immunohistochemical labeling of GnRH fibers revealed varicosities along terminal nerve axons near the amacrine cell layer and near cells immunoreactive for tyrosine hydroxylase, a dopaminergic cell marker. This finding supports an existing model that the terminal nerve forms synapses with dopaminergic interplexiform cells. Surprisingly, the type 2 GnRH receptor (GnRH-R2) was abundantly expressed in ganglion cells, which lie along the direct pathway of visual information to the brain. These data suggest that GnRH from the TN could broadly influence processing of retinal signals both in lateral processing circuits through GnRH-R1 and in the vertical throughput pathway through GnRH-R2.

Animals↗

PubMed2005

Behavioral coping strategies in a cichlid fish: the role of social status and acute stress response in direct and displaced aggression.

The African cichlid fish, Astatotilapia burtoni, has a complex social system with a sophisticated social hierarchy that offers unique opportunities to understand how social rank and its physiological substrates relate to behavioral strategies. In A. burtoni, a small fraction of the males are dominant (T, territorial), as distinguished by being large, brightly colored, reproductively active, and aggressively defending territories. In contrast, the majority of males are non-dominant (NT, non-territorial), being smaller, drably colored, sexually immature, and typically schooling with females. The social system is regulated by aggressive interactions between males and behavioral responses to aggression can be direct or displaced with respect to the animal that acts. To determine whether direct and displaced behaviors are differentially exhibited by T and NT males, individuals were shown a video presentation of a dominant male displaying aggressively. Analysis of aggressive acts toward the video display and displaced activity toward a tank mate revealed that T males exhibited more direct behavior (toward the video display), while NT males engaged in more displaced behavior (toward tank mates). Because similar experiments with primates suggest that shifts in behavioral strategies are linked to changes in the stress response (as measured by circulating cortisol levels), we measured cortisol levels of T and NT males following exposure to the aggressive stimulus. Although in some animals subordinate males are reported to have higher cortisol levels, here we show that in A. burtoni the endocrine response to specific situations can vary considerably even among animals of the same status. Interestingly, NT males with intermediate cortisol levels showed more directed behavior while NT males with both high and low cortisol levels showed more displaced. This suggests an optimal physiological stress response in NT males that predisposes them to challenge aggressors perhaps making it more likely for them to ascend in status.

Acute Disease↗

PubMed2005

Evolutionary conservation of the egr-1 immediate-early gene response in a teleost.

Immediate-early gene expression is a key part of a neuron's response to behaviorally relevant stimuli and, as a result, localization of immediate-early gene expression can be a useful marker for neural activity. We characterized the immediate-early gene egr-1 (also called zif268, NGFI-A, krox-24, ZENK) in the teleost Astatotilapia (Haplochromis) burtoni. We compared the A. burtoni egr-1 predicted protein sequence to that of other vertebrates, characterized its gene expression time course, and localized its induced expression throughout the brain. The A. burtoni egr-1 predicted protein shared putative functional domains with egr-1 of other vertebrates and shared 81% sequence similarity with zebrafish and 66% with mouse. We identified distinct mammalian and teleost inserts rich in serine residues within one activation domain, suggesting convergent responses to selection pressures to increase the number of serine residues in this region. Functionally, we found that A. burtoni egr-1 gene expression peaked near 30 minutes after pharmacological stimulation and thereby displayed the transient expression above basal levels characteristic of egr-1 expression in birds and mammals. Finally, we observed distinct patterns of egr-1 gene induction in the brain by natural and pharmacological stimuli. Unstimulated males had very low expression levels of egr-1, whereas males stimulated by their normal environment showed higher levels of expression specific to particular brain regions. Males injected with a glutamate receptor agonist also had region-specific induction of egr-1 expression. We conclude that the egr-1 immediate-early gene response is evolutionarily conserved and will, therefore, be useful for identifying functional neural responses in nontraditional model species.

Animals↗

PubMed2005

IGF-1 produced by cone photoreceptors regulates rod progenitor proliferation in the teleost retina.

Teleost eyes grow throughout life by adding neurons and stretching extant tissue. New retinal neurons of all types are added at the ciliary margin and new rod photoreceptors are inserted throughout retina in the outer nuclear layer (ONL). New rod photoreceptors result from the division of progenitor cells located in the ONL amidst functioning rod photoreceptor cell nuclei, but it is not known how new rod addition is regulated. Previous experiments using an organotypic retinal slice preparation revealed that insulin-like growth factor 1 (IGF-1) up-regulates the division of the rod progenitor cells [Dev. Brain Res. 76 (1993) 183], but the site of IGF-1 action was unknown. Here, we show where in the retina IGF-1 is made, where IGF receptors are located, and we identify the role of IGF-1 in adult retinal rod neurogenesis with both gain-and loss-of-function experiments. We found that IGF-1 is expressed by cone photoreceptor cells and its abundance varies with a daily rhythm, being significantly higher at night. In vivo application of exogenous IGF-1 increases rod progenitor cell division, an effect that is greater at night than during the day. We also show that inhibiting the function of IGF receptors decreases proliferation of rod progenitor cells. Finally, we show that IGF receptors are located on rod progenitor cells as well as on cone and rod photoreceptors. Taken together, these data suggest that the rhythmic production and release of IGF-1 plays a role in regulating the insertion of new rod photoreceptors into the retina. The diurnal change in IGF-1 abundance and effects of exogenous IGF-1 are consistent with the previous demonstration that rod progenitor cell division is threefold greater at night than in the day [Brain Res. 673 (1995) 119; Brain Res. 712 (1996) 40]. We also show that the insertion of new rod photoreceptors at the central edge of the ciliary neurogenic zone very likely also depends on IGF-1 production by cone photoreceptors. We propose that addition of new rod photoreceptors into the functioning retina is regulated through a feedback mechanism mediated at least in part via the IGF-1 produced in the cone photoreceptors.

Animals↗

PubMed2005

Comprehensive algorithm for quantitative real-time polymerase chain reaction.

Quantitative real-time polymerase chain reactions (qRT-PCR) have become the method of choice for rapid, sensitive, quantitative comparison of RNA transcript abundance. Useful data from this method depend on fitting data to theoretical curves that allow computation of mRNA levels. Calculating accurate mRNA levels requires important parameters such as reaction efficiency and the fractional cycle number at threshold (CT) to be used; however, many algorithms currently in use estimate these important parameters. Here we describe an objective method for quantifying qRT-PCR results using calculations based on the kinetics of individual PCR reactions without the need of the standard curve, independent of any assumptions or subjective judgments which allow direct calculation of efficiency and CT. We use a four-parameter logistic model to fit the raw fluorescence data as a function of PCR cycles to identify the exponential phase of the reaction. Next, we use a three-parameter simple exponent model to fit the exponential phase using an iterative nonlinear regression algorithm. Within the exponential portion of the curve, our technique automatically identifies candidate regression values using the P-value of regression and then uses a weighted average to compute a final efficiency for quantification. For CT determination, we chose the first positive second derivative maximum from the logistic model. This algorithm provides an objective and noise-resistant method for quantification of qRT-PCR results that is independent of the specific equipment used to perform PCR reactions.

Algorithms↗

PubMed2004

Functional mapping of the auditory midbrain during mate call reception.

We examined patterns of neural activity as assayed by changes in gene expression to localize representation of acoustic mating signals in the auditory midbrain of frogs. We exposed wild-caught male Physalaemus pustulosus to conspecific mating calls that vary in their behavioral salience, nonsalient mating calls, or no sound. We measured expression of the immediate early gene egr-1 (also called ZENK, zif268, NGFI-A, and krox-24) throughout the torus semicircularis, the auditory midbrain homolog of the inferior colliculus. Differential egr-1 induction in response to the acoustic stimuli occurred in the laminar, midline, and principal nuclei of the torus semicircularis, whereas the ventral region did not show significant effects of stimulus. The laminar nucleus differentially responded to conspecific mating calls compared with nonsalient mating calls, whereas the midline and principal nuclei responded preferentially to one of two conspecific calls. These responses were not explained by simple acoustic properties of the stimuli, and they demonstrate a functional heterogeneity of auditory processing of complex biological signals within the frog midbrain. Moreover, using analyses that assess the ability of the torus semicircularis as a whole to discriminate among acoustic stimuli, we found that activity patterns in the four regions together provide more information about biologically relevant acoustic stimuli than activity in any single region.

Animals↗

PubMed2004

Timing and location of rhodopsin expression in newly born rod photoreceptors in the adult teleost retina.

Labeling of newly divided retinal cells with bromodeoxyuridine (BrdU) and a rhodopsin mRNA probe revealed that rhodopsin is first expressed by new rod photoreceptors 2 days after cell birth in an adult cichlid fish. Most new cells that expressed rhodopsin had nuclei located in the vitreal half of the outer nuclear layer (ONL), lending further support to the hypothesis that movement from scleral to vitreal ONL is associated with rod differentiation.

Age Factors↗

PubMed2004

Social regulation of the electrical properties of gonadotropin-releasing hormone neurons in a cichlid fish (Astatotilapia burtoni).

Variation in reproductive capacity is common across the lives of all animals. In vertebrates, hypothalamic neurons that secrete GnRH are a primary mediator of such reproductive plasticity. Since social interactions suppress gonadal maturity in the African cichlid fish, Astatotilapia (Haplochromis) burtoni, we investigated whether the electrical properties of GnRH neurons were also socially regulated. Adult A. burtoni males are either territorial (T) and reproductively active or nonterritorial (NT) and reproductively regressed, depending upon their social environment. We compared the basic electrical properties of hypothalamic GnRH neurons from T and NT males using whole-cell electrophysiology in vitro. GnRH neurons were spontaneously active and exhibited several different activity patterns. A small fraction of neurons exhibited episodic activity patterns, which have been described in GnRH neurons from mammals. The type of activity pattern and spontaneous firing rate did not vary with reproductive capacity; however, several basic electrical properties were different. Neurons from T males were larger than those from NT males and had higher membrane capacitance and lower input resistance. In neurons from NT males, action potential duration was significantly longer and after-hyperpolarization characteristics were diminished, which led to a tendency for neurons from NT males to fire less rapidly in response to current injection. We predict this could serve to decrease GnRH release in NT males. These data are the first electrophysiological characterization of hypothalamic GnRH neurons in a nonmammalian species and provide evidence for several changes in electrical properties with reproductive state.

Action Potentials↗

PubMed2004

How the brain processes social information: searching for the social brain.

Because information about gender, kin, and social status are essential for reproduction and survival, it seems likely that specialized neural mechanisms have evolved to process social information. This review describes recent studies of four aspects of social information processing: (a) perception of social signals via the vomeronasal system, (b) formation of social memory via long-term filial imprinting and short-term recognition, (c) motivation for parental behavior and pair bonding, and (d) the neural consequences of social experience. Results from these studies and some recent functional imaging studies in human subjects begin to define the circuitry of a "social brain." Such neurodevelopmental disorders as autism and schizophrenia are characterized by abnormal social cognition and corresponding deficits in social behavior; thus social neuroscience offers an important opportunity for translational research with an impact on public health.

Animals↗