Forebrain Function Research Articles

Developmental studies of avian brain organization.

Avian brain organization or brain Bauplan is identical with that of vertebrates in general. This essay visits avian studies that contained advances or discussions about brain organization, trying to explain critically what they contributed. In order to start from a specific background, the new prevailing paradigm as regards brain organization, the prosomeric model, is presented first. Next a brief historic survey is made of how ideas on this topic evolved from the start of modern neuromorphology at the end of the 19th century. Longitudinal zonal organization with or without transverse segmentation (neuromeres) was the first overall concept applied to the brain. The idea of neuromeric structure later decayed in favour of a columnar model. This emphasized functional correlations rather than causal developmental content, assimilating forebrain functions to hindbrain ones. Though it became prevalent in the post-world-war period of neuroscience, in the last decades of the 20th century advances in molecular biology allowed developmental genes to be mapped, and it became evident that gene expression patterns support the old neuromeric model rather than the columnar one. This was also corroborated by modern experimental approaches (fate-mapping and analysis of patterning).

A lateralized functional auditory network is involved in anuran sexual selection.

Right ear advantage (REA) exists in many land vertebrates in which the right ear and left hemisphere preferentially process conspecific acoustic stimuli such as those related to sexual selection. Although ecological and neural mechanisms for sexual selection have been widely studied, the brain networks involved are still poorly understood. In this study we used multi-channel electroencephalographic data in combination with Granger causal connectivity analysis to demonstrate, for the first time, that auditory neural network interconnecting the left and right midbrain and forebrain function asymmetrically in the Emei music frog (Babina daunchina), an anuran species which exhibits REA. The results showed the network was lateralized. Ascending connections between the mesencephalon and telencephalon were stronger in the left side while descending ones were stronger in the right, which matched with the REA in this species and implied that inhibition from the forebrainmay induce REA partly. Connections from the telencephalon to ipsilateral mesencephalon in response to white noise were the highest in the non-reproductive stage while those to advertisement calls were the highest in reproductive stage, implying the attention resources and living strategy shift when entered the reproductive season. Finally, these connection changes were sexually dimorphic, revealing sex differences in reproductive roles.

Expression of aromatase in the embryonic brain of the olive ridley sea turtle (Lepidochelys olivacea), and the effect of bisphenol-A in sexually differentiated embryos.

Brain aromatase participates in several biological processes, such as regulation of the reproductive-endocrine axis, memory, stress, sexual differentiation of the nervous system, male sexual behavior, and brain repair. Here we report the isolation and expression of brain aromatase in olive ridley sea turtle (Lepidochelys olivacea) embryos incubated at male- and female-promoting temperatures (MPT and FPT, respectively), at the thermosensitive period (TSP) and the sex-differentiated period. Also, aromatase expression was assessed in differentiated embryos exposed to bisphenol-A (BPA) during the TSP. BPA is a monomer of polycarbonate plastics and is considered an endocrine-disrupting compound. Normal aromatase expression was measured in both forebrain and hindbrain, showing higher expression levels in the forebrain of differentiated embryos at both incubation temperatures. Although no significant differences were detected in the hindbrain, expression was slightly higher at MPT. BPA did not affect aromatase expression neither in forebrains or hindbrains from embryos incubated at MPT, whereas at FPT an inverted U-shape curve was observed in forebrains with significant differences at lower concentrations, whereas in hindbrains a non-significant increment was observed at higher concentrations. Our data indicate that both incubation temperature and developmental stage are critical factors affecting aromatase expression in the forebrain. Because of the timing and location of aromatase expression in the brain, we suggest that brain aromatase may participate in the imprinting of sexual trends related to reproduction and sexual behavior at the onset of sex differentiation, and BPA exposure may impair aromatase function in the female forebrain.

Insights into rapid modulation of neuroplasticity by brain estrogens.

Converging evidence from cellular, electrophysiological, anatomic, and behavioral studies suggests that the remodeling of synapse structure and function is a critical component of cognition. This modulation of neuroplasticity can be achieved through the actions of numerous extracellular signals. Moreover, it is thought that it is the integration of different extracellular signals regulation of neuroplasticity that greatly influences cognitive function. One group of signals that exerts powerful effects on multiple neurologic processes is estrogens. Classically, estrogens have been described to exert their effects over a period of hours to days. However, there is now increasing evidence that estrogens can rapidly influence multiple behaviors, including those that require forebrain neural circuitry. Moreover, these effects are found in both sexes. Critically, it is now emerging that the modulation of cognition by rapid estrogenic signaling is achieved by activation of specific signaling cascades and regulation of synapse structure and function, cumulating in the rewiring of neural circuits. The importance of understanding the rapid effects of estrogens on forebrain function and circuitry is further emphasized as investigations continue to consider the potential of estrogenic-based therapies for neuropathologies. This review focuses on how estrogens can rapidly influence cognition and the emerging mechanisms that underlie these effects. We discuss the potential sources and the biosynthesis of estrogens within the brain and the consequences of rapid estrogenic-signaling on the remodeling of neural circuits. Furthermore, we argue that estrogens act via distinct signaling pathways to modulate synapse structure and function in a manner that may vary with cell type, developmental stage, and sex. Finally, we present a model in which the coordination of rapid estrogenic-signaling and activity-dependent stimuli can result in long-lasting changes in neural circuits, contributing to cognition, with potential relevance for the development of novel estrogenic-based therapies for neurodevelopmental or neurodegenerative disorders.

Effects of oral 5‐hydroxytryptophan on a standardized planning task: insight into possible dopamine/serotonin interactions in the forebrain

Several studies have suggested that exogenous administration of the serotonin precursor 5-hydroxytryptophan (5-HTP) can result in the ectopic production of serotonin in dopaminergic neurons and a concomitant reduction in dopamine release. This study tested this hypothesis using the Tower of London (TOL), a test of planning and executive control that is sensitive to changes in forebrain dopamine activity, but insensitive to alterations in serotonin. A sample of 68 undergraduates participated, and each received either three 50-mg 5-HTP capsules or placebos, and completed the TOL following a set absorption period. 5-HTP significantly lengthened the average time needed to complete each of the 10 trials of the TOL. 5-HTP did not affect accuracy on this task. Oral exogenous 5-HTP disrupts dopaminergic function in the human forebrain.

Estradiol Selectively Enhances Auditory Function in Avian Forebrain Neurons

Sex steroids modulate vertebrate sensory processing, but the impact of circulating hormone levels on forebrain function remains unclear. We tested the hypothesis that circulating sex steroids modulate single-unit responses in the avian telencephalic auditory nucleus, field L. We mimicked breeding or nonbreeding conditions by manipulating plasma 17β-estradiol levels in wild-caught female Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii). Extracellular responses of single neurons to tones and conspecific songs presented over a range of intensities revealed that estradiol selectively enhanced auditory function in cells that exhibited monotonic rate level functions to pure tones. In these cells, estradiol treatment increased spontaneous and maximum evoked firing rates, increased pure tone response strengths and sensitivity, and expanded the range of intensities over which conspecific song stimuli elicited significant responses. Estradiol did not significantly alter the sensitivity or dynamic ranges of cells that exhibited non-monotonic rate level functions. Notably, there was a robust correlation between plasma estradiol concentrations in individual birds and physiological response properties in monotonic, but not non-monotonic neurons. These findings demonstrate that functionally distinct classes of anatomically overlapping forebrain neurons are differentially regulated by sex steroid hormones in a dose-dependent manner.

A Visual Description of the Dissection of the Cerebral Surface Vasculature and Associated Meninges and the Choroid Plexus from Rat Brain

This video presentation was created to show a method of harvesting the two most important highly vascular structures, not residing within the brain proper, that support forebrain function. They are the cerebral surface (superficial) vasculature along with associated meninges (MAV) and the choroid plexus which are necessary for cerebral blood flow and cerebrospinal fluid (CSF) homeostasis. The tissue harvested is suitable for biochemical and physiological analysis, and the MAV has been shown to be sensitive to damage produced by amphetamine and hyperthermia 1,2. As well, the major and minor cerebral vasculatures harvested in MAV are of potentially high interest when investigating concussive types of head trauma. The MAV dissected in this presentation consists of the pial and some of the arachnoid membrane (less dura) of the meninges and the major and minor cerebral surface vasculature. The choroid plexus dissected is the structure that resides in the lateral ventricles as described by Oldfield and McKinley3,4,5,6. The methods used for harvesting these two tissues also facilitate the harvesting of regional cortical tissue devoid of meninges and larger cerebral surface vasculature, and is compatible with harvesting other brain tissues such as striatum, hypothalamus, hippocampus, etc. The dissection of the two tissues takes from 5 to 10 min total. The gene expression levels for the dissected MAV and choroid plexus, as shown and described in this presentation can be found at GSE23093 (MAV) and GSE29733 (choroid plexus) at the NCBI GEO repository. This data has been, and is being, used to help further understand the functioning of the MAV and choroid plexus and how neurotoxic events such as severe hyperthermia and AMPH adversely affect their function.

A Visual Description of the Dissection of the Cerebral Surface Vasculature and Associated Meninges and the Choroid Plexus from Rat Brain

This video presentation was created to show a method of harvesting the two most important highly vascular structures, not residing within the brain proper, that support forebrain function. They are the cerebral surface (superficial) vasculature along with associated meninges (MAV) and the choroid plexus which are necessary for cerebral blood flow and cerebrospinal fluid (CSF) homeostasis. The tissue harvested is suitable for biochemical and physiological analysis, and the MAV has been shown to be sensitive to damage produced by amphetamine and hyperthermia 1,2. As well, the major and minor cerebral vasculatures harvested in MAV are of potentially high interest when investigating concussive types of head trauma. The MAV dissected in this presentation consists of the pial and some of the arachnoid membrane (less dura) of the meninges and the major and minor cerebral surface vasculature. The choroid plexus dissected is the structure that resides in the lateral ventricles as described by Oldfield and McKinley3,4,5,6. The methods used for harvesting these two tissues also facilitate the harvesting of regional cortical tissue devoid of meninges and larger cerebral surface vasculature, and is compatible with harvesting other brain tissues such as striatum, hypothalamus, hippocampus, etc. The dissection of the two tissues takes from 5 to 10 min total. The gene expression levels for the dissected MAV and choroid plexus, as shown and described in this presentation can be found at GSE23093 (MAV) and GSE29733 (choroid plexus) at the NCBI GEO repository. This data has been, and is being, used to help further understand the functioning of the MAV and choroid plexus and how neurotoxic events such as severe hyperthermia and AMPH adversely affect their function.

Effects of prenatal stress and monoaminergic perturbations on the expression of serotonin 5-HT4 and adrenergic β2 receptors in the embryonic mouse telencephalon

The serotonin 5-HT4 receptor (5-HT4R) is coded by a complex gene that produces four mRNA splice variants in mice (5-HT4(a)R, 5-HT4(b)R, 5-HT4(e)R, 5-HT4(f)R). This receptor has highly dynamic expression in brain development and its splice variants differ in their developmental trajectories. Since 5-HT4Rs are important in forebrain function (including forebrain control of serotonergic activity in the brainstem), we investigated the susceptibility of 5-HT4R expression in the mouse embryonic telencephalon to prenatal maternal stress and altered serotonin (5-hydroxytryptamine, 5-HT) levels. Because the gene coding the adrenergic β2 receptor (β2AR) is embedded in the 5-HT4R gene, we also investigated whether 5-HT4R mRNA levels were modulated by selective β2AR agents. Timed-pregnant C57BL/6 mice were treated beginning at embryonic day (E) 14 and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to assess the mRNA levels of all 5-HT4R splice variants and β2AR in the embryonic telencephalon at E17. Maternal prenatal stress and 5-HT depletion with pCPA, a tryptophan hydroxylase inhibitor, reduced the levels of the 5-HT4(b)R splice variant. Terbutaline (a selective β2AR agonist) and ICI 118,551 (a selective β2AR antagonist) had no effect on β2AR and 5-HT4R mRNA levels. These results show that prenatal stress and reduced 5-HT levels can alter 5-HT4R expression in the developing forebrain and that some 5-HT4R splice variants may be more susceptible than others.

Processed Electroencephalogram and Depth of Anesthesia

Processed Electroencephalogram and Depth of Anesthesia

In vitro neuropharmacological evaluation of penitrem-induced tremorgenic syndromes: Importance of the GABAergic system

The effects of the fungal neurotoxin penitrem A on the GABAergic and glutamatergic systems in rat brain were evaluated. Penitrem A inhibited binding of the GABA A-receptor ligand [ 3H]TBOB to rat forebrain and cerebellar membrane preparations with IC 50 (half maximal inhibitory concentration) values of 11 and 9 μM, respectively. Furthermore, penitrem A caused a concentration-dependent increase of [ 3H]flunitrazepam and [ 3H]muscimol binding in rat forebrain, but not in cerebellar preparations. The stimulation of [ 3H]flunitrazepam binding by penitrem A was abolished by the addition of GABA. In cerebellar preparations, a different pharmacological profile was found, with penitrem A allosterically inhibiting [ 3H]TBOB binding by interacting with a bicuculline-sensitive site. Moreover, penitrem A inhibited the high affinity uptake of GABA and glutamate into cerebellar synaptosomes with IC 50 values of 20 and 47 μM, respectively. The toxin showed no effect on NMDA or AMPA glutamate receptor binding. In conclusion, our results suggest that penitrem A exerts region-specific effects in the brain, leading to positive modulation of GABA A-receptor function in forebrain. Conversely, penitrem A may act as a bicuculline-like convulsant in cerebellum.

Correlates of birth origin effects on the development of stereotypic behaviour in striped mice, Rhabdomys

The behaviour and physiology of wild animals born in zoos, laboratories and breeding centres can differ substantially from that of their wild-caught (WC) conspecifics. For instance, captive-born (CB) animals are typically more prone to developing abnormal repetitive behaviours. In captive striped mice, Rhabdomys , we first confirmed that birth origin predicted the emergence of stereotypic behaviour (SB), with CB mice being most at risk. Second, to investigate correlates of this birth origin effect, we tested WC and CB striped mice in behavioural tasks to quantify fear/anxiety, activity and perseveration, and measured faecal corticosterone to assess physiological stress. WC mice proved more fearful and less active than CB animals, and had higher levels of faecal corticosterone metabolites. These effects, however, were unrelated to SB. WC mice were also less perseverative and more behaviourally flexible than CB animals, traits that covary with SB. Third, a retrospective analysis of laboratory records showed that SB incidence was significantly lower in adult-caught than juvenile-caught striped mice, with juvenile males being the most severely affected by early removal from the wild. In conclusion, our results indicate that adult, but not juvenile WC striped mice are typically protected against SB development in captivity, despite having poorer welfare than their CB conspecifics. They also reveal profound behavioural changes in CB mice, changes suggestive of altered forebrain function, a hypothesis now needing direct testing.

Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain

Cytosine methylation is the major covalent modification of mammalian genomic DNA and plays important roles in transcriptional regulation. The molecular mechanism underlying the enzymatic removal of this epigenetic mark, however, remains elusive. Here, we show that 5-methylcytosine (5mC) hydroxylase TET1, by converting 5mCs to 5-hydroxymethylcytosines (5hmCs), promotes DNA demethylation in mammalian cells through a process that requires the base excision repair pathway. Though expression of the 12 known human DNA glycosylases individually did not enhance removal of 5hmCs in mammalian cells, demethylation of both exogenously introduced and endogenous 5hmCs is promoted by the AID (activation-induced deaminase)/APOBEC (apolipoprotein B mRNA-editing enzyme complex) family of cytidine deaminases. Furthermore, Tet1 and Apobec1 are involved in neuronal activity-induced, region-specific, active DNA demethylation and subsequent gene expression in the dentate gyrus of the adult mouse brain in vivo. Our study suggests a TET1-induced oxidation-deamination mechanism for active DNA demethylation in mammals.

Loss of procollagen IIA from the anterior mesendoderm disrupts the development of mouse embryonic forebrain

Morphogenesis of the mammalian forebrain is influenced by the patterning activity of signals emanating from the anterior mesendoderm. In this study, we show that procollagen IIA (IIA), an isoform of the cartilage extracellular matrix protein encoded by an alternatively spliced transcript of Col2a1, is expressed in the prechordal plate and the anterior definitive endoderm. In the absence of IIA activity, the null mutants displayed a partially penetrant phenotype of loss of head tissues, holoprosencephaly, and loss of mid-facial structures, which is associated with reduced sonic hedgehog (Shh) expression in the prechordal mesoderm. Genetic interaction studies reveal that IIA function in forebrain and face development does not involve bone morphogenetic protein receptor 1A (BMPR1A)- or NODAL-mediated signaling activity.

Relevance of norepinephrine-dopamine interactions in the treatment of major depressive disorder.

Central dopaminergic and noradrenergic systems play essential roles in controlling several forebrain functions. Consequently, perturbations of these neurotransmissions may contribute to the pathophysiology of neuropsychiatric disorders. For many years, there was a focus on the serotonin (5‐HT) system because of the efficacy of selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants in the treatment of major depressive disorder (MDD). Given the interconnectivity within the monoaminergic network, any action on one system may reverberate in the other systems. Analysis of this network and its dysfunctions suggests that drugs with selective or multiple modes of action on dopamine (DA) and norepinephrine (NE) may have robust therapeutic effects. This review focuses on NE‐DA interactions as demonstrated in electrophysiological and neurochemical studies, as well as on the mechanisms of action of agents with either selective or dual actions on DA and NE. Understanding the mode of action of drugs targeting these catecholaminergic neurotransmitters can improve their utilization in monotherapy and in combination with other compounds particularly the SSRIs. The elucidation of such relationships can help design new treatment strategies for MDD, especially treatment‐resistant depression.

Frustration and perseveration in stereotypic captive animals: Is a taste of enrichment worse than none at all?

Stereotypic behaviours are common in animals in impoverished housing, arising from two complementary processes: (1) thwarted attempts to perform motivated behaviours; (2) forebrain dysfunction impeding normal behavioural inhibition. When enriched animals are moved to impoverished housing, they are sometimes protected against developing stereotypic behaviour, but in other cases become even more stereotypic than animals housed lifelong without enrichment. Negative contrast-induced frustration must occur in both scenarios. We hypothesise that sustained behavioural responses to this frustration are prevented in the former by normalised forebrain function, but exacerbated in the latter by forebrain dysfunction. ICRCD-1 mice reared in enriched or standard cages were re-caged at 3 months to standard conditions. Here, previously-enriched mice became far more stereotypic than mice reared from birth in such conditions. To investigate the role of frustration, we assessed both corticosterone output and motivation (break-point) to regain enrichments. We also assessed perseveration via extinction learning. As predicted, previously-enriched mice were as perseverative as standard-raised mice, and frustration seemed to play a causal role in their exacerbated stereotypic behaviour. Previously-enriched mice showed higher motivations to access enrichments, and only in this group did these correlate with corticosterone levels after re-caging; furthermore only in previously-enriched mice did corticosterone responses to re-caging predict stereotypic behaviour 30 days later (males only). All results need replicating and further investigation. However, they suggest for the first time that individual risk factors related to the HPA axis predict stereotypic behaviour following enrichment-removal, and that previously-enriched mice have lasting motivational differences from standard-raised mice, suggesting sustained behavioural effects related to the frustration of enrichment-loss.

Expression of vascular endothelial growth factor receptor‐3 mRNA in the rat developing forebrain and retina

Vascular endothelial growth factor receptor (VEGFR)-3, a receptor for VEGF-C and VEGF-D, is expressed in neural progenitor cells, but there has been no comprehensive study of its distribution in the developing brain. Here, the temporal and cell-specific expression of VEGFR-3 mRNA was studied in the developing rat forebrain and eye. Expression appeared along the ventricular and subventricular zones of the lateral and third ventricles showing ongoing neurogenesis as early as embryonic day 13 but was progressively down-regulated during development and remained in the subventricular zone and rostral migratory stream of the adult forebrain. VEGFR-3 expression was also detectable in some differentiating and postmitotic neurons in the developing cerebral cortex, including Cajal-Retzius cells, cortical plate neurons, and subplate neurons. Expression in the subplate increased significantly during the early postnatal period but was absent by postnatal day 14. It was also highly expressed in nonneural tissues of the eye during development, including the retinal pigment epithelium, the retinal ciliary margin, and the lens, but persisted in a subset of cells in the pigmented ciliary epithelium of the adult eye. In contrast, there was weak or undetectable expression in the early neural retina, but a subset of retinal neurons in the postnatal and mature retina showed intense signals. These unique spatiotemporal mRNA expression patterns suggest that VEGFR-3 might mediate the regulation of both neurogenesis and adult neuronal function in the rat forebrain and eye.

Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor-Mediated Mechanisms

Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which GABA type A (GABA(A)) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild-type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABA(A) receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild-type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, spontaneous IPSC amplitude and frequency and the expression of selective GABA(A) receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- versus ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu.

Glutamate elicits release of BDNF from basal forebrain astrocytes in a process dependent on metabotropic receptors and the PLC pathway

A key neurotrophin responsible for the survival and function of basal forebrain (BF) cholinergic neurons is brain-derived neurotrophic factor (BDNF). A number of studies now indicate that a source of this factor may be BF astrocytes. This study was designed to define the role of BF-astrocyte-derived BDNF on cholinergic neurons. Moreover, it investigated regulatory events that modulate BDNF content and release. In initial work BDNF derived from BF-astrocyte-conditioned medium (ACM) was found to increase both numbers of BF acetylcholinesterase (AChE+) cholinergic neurons and the cholinergic synthetic enzyme choline acetyltransferase (ChAT). Western blots, immunocytochemistry and pharmacological inhibition studies revealed that glutamate, through group I metabotropic glutamate receptors (mGluR), increases the intracellular levels of BDNF in BF astrocytes in culture, as well as its release. Furthermore, the release of BDNF is mediated by the actions of PLC, IP3 and internal stores of Ca2+. These results suggest that BF astrocytes serve as local sources of BDNF for cholinergic neurons, and that they may be regulated as such by the neuronal signal, glutamate, through the mediation of group I metabotropic receptors and the PLC pathway.

Association of the Dusp6 (Mkp3) Gene With Mouse Brain Weight and Forebrain Structure

PYST1/MKP3 is a negative feedback modulator of fibroblast growth factor 8 (Fgf8) signaling in the mammalian isthmic organizer of the brain, which affects the development of the midbrain and the hindbrain. The Dusp6 (Mkp3) gene is also highly expressed in the mouse embryonic forebrain. However, its role in forebrain development and function remains largely unknown. In this study, association analyses were preformed in silico between the variation I62M (rs13480726) of the Dusp6 (Mkp3) gene and the mouse forebrain weight/structure in 385 mice of 20 strains. It was found that I62M (allele A) was associated with reduced mouse forebrain structure in both sexes and lower brain weight in males.