Characterization of the dopamine system in the brain of the túngara frog, Physalaemus pustulosus

Dopamine is an evolutionarily ancient neurotransmitter that plays an essential role in mediating behavior. In vertebrates, dopamine is central to the mesolimbic reward system, a neural network concerned with the valuation of stimulus salience, and to the nigrostriatal motor system and hypothalamic nuclei involved in the regulation of locomotion and social behavior. In amphibians, dopaminergic neurons have been mapped out in several species, yet the distribution of dopaminoreceptive cells is unknown. The túngara frog, Physalaemus pustulosus, is an excellent model system for the study of neural mechanisms by which valuations of stimuli salience and social decisions are made, especially in the context of mate choice. In order to better understand where dopamine acts to regulate social decisions in this species, we have determined the distribution of putative dopaminergic cells (using tyrosine hydroxylase immunohistochemistry) and cells receptive to dopaminergic signaling (using DARPP-32 immunohistochemistry) throughout the brain of P. pustulosus. The distribution of dopaminergic cells was comparable to other anurans. DARPP-32 immunoreactivity was identified in key brain regions known to modulate social behavior in other vertebrates including the proposed anuran homologues of the mammalian amygdalar complex, nucleus accumbens, hippocampus, striatum, preoptic area, anterior hypothalamus, ventromedial hypothalamus, and ventral tegmental area/substantia nigra pars compacta. Due to its widespread distribution, DARPP-32 likely also plays many roles in non-limbic brain regions that mediate non-social information processing. These results significantly extend our understanding of the distribution of the dopaminergic system in the anuran brain and beyond.     

On the history of lacunes, etat criblé, and the white matter lesions of vascular dementia

The history of lesions associated with vascular dementia (17th to 19th century) is reviewed. Recognition of ischemic and hemorrhagic stroke types dates back to the 17th century; however, at that time a third type ('cerebral congestion') emerged as the most common form of apoplexy. This entity vanished as arterial hypertension became established with the introduction of the sphygmomanometer (1905). Before the 19th century, apoplexy was considered a uniformly fatal disease, although Willis first recognized post-stroke dementia in 1672. Dechambre (1838) first reported 'lacunes' in stroke survivors with small cerebral softenings. Durand-Fardel (1842) described interstitial atrophy of the brain (leukoaraiosis) and état criblé (cribriform state) reflecting chronic cerebral congestion. In 1894, Alzheimer and Binswanger identified 'arteriosclerotic brain atrophy,' a form of vascular dementia characterized by 'miliary apoplexies' (lacunes). Also in 1894, Binswanger described the disease that now bears his name. In 1901, Pierre Marie coined the name état lacunaire (lacunar state) for the clinical syndrome of elderly patients with multiple lacunes.     

Sesquicentenary of the birthday of Santiago Ramón y Cajal,the father of modern neuroscience

The appearance of Santiago Ramón y Cajal in the world of neuroscience provoked a radical change in the course of its history. Cajal's studies of the microanatomy of virtually the whole CNS and his observations regarding degeneration and regeneration, together with his theories about the function, development and plasticity of the nervous system, had a profound impact on researchers of his era. These studies represent the roots of what are today some of the most exciting areas of discovery in terms of the structure and function of the brain in both sickness and health.     

Neuron theory, the cornerstone of neuroscience, on the centenary of the Nobel Prize award to Santiago Ramón y Cajal

Exactly 100 years ago, the Nobel Prize for Physiology and Medicine was awarded to Santiago Ramón y Cajal, “in recognition of his meritorious work on the structure of the nervous system”. Cajal's great contribution to the history of science is undoubtedly the postulate of neuron theory. The present work makes a historical analysis of the circumstances in which Cajal formulated his theory, considering the authors and works that influenced his postulate, the difficulties he encountered for its dissemination, and the way it finally became established. At the time when Cajal began his neurohistological studies, in 1887, Gerlach's reticular theory (a diffuse protoplasmic network of the grey matter of the nerve centres), also defended by Golgi, prevailed among the scientific community. In the first issue of the Revista Trimestral de Histología Normal y Patológica (May, 1888), Cajal presented the definitive evidence underpinning neuron theory, thanks to staining of the axon of the small, star-shaped cells of the molecular layer of the cerebellum of birds, whose collaterals end up surrounding the Purkinje cell bodies, in the form of baskets or nests. He thus demonstrated once and for all that the relationship between nerve cells was not one of continuity, but rather of contiguity. Neuron theory is one of the principal scientific conquests of the 20th century, and which has withstood, with scarcely any modifications, the passage of more than a 100 years, being reaffirmed by new technologies, as the electron microscopy. Today, no neuroscientific discipline could be understood without recourse to the concept of neuronal individuality and nervous transmission at a synaptic level, as basic units of the nervous system.     

Trump,Freud, the Puzzle of Femininity—and #MeToo

Abstract

Beneath Donald Trump’s repudiation of democratic values and practically all vestiges of Obama’s legacy (which has spurred a clamor to repudiate Trump) lies a repudiation of the feminine. It underwrites Trump’s cult of hypermasculinity and enables his exploitation of masculine insecurity, along with the gutting of climate protections and reproductive rights. Freud believed the repudiation of femininity was “psychological bedrock” (for both sexes); this article argues that, on the contrary, we have no fundamental need to repudiate the feminine. In fact, to embrace the feminine, in both material and symbolic ways, would be to open an important space for a more democratic polity. But claiming the feminine is so threatening that some, perhaps most, would prefer to lock it up and deny its vast and elemental erotic power and democratizing possibility. #MeToo unleashes the feminine potential for an emancipatory politics beyond patriarchy.     

What are the computations of the cerebellum,the basal ganglia and the cerebral cortex?

The classical notion that the cerebellum and the basal ganglia are dedicated to motor control is under dispute given increasing evidence of their involvement in non-motor functions. Is it then impossible to characterize the functions of the cerebellum, the basal ganglia and the cerebral cortex in a simplistic manner? This paper presents a novel view that their computational roles can be characterized not by asking what are the “goals” of their computation, such as motor or sensory, but by asking what are the “methods” of their computation, specifically, their learning algorithms. There is currently enough anatomical, physiological, and theoretical evidence to support the hypotheses that the cerebellum is a specialized organism for supervised learning, the basal ganglia are for reinforcement learning, and the cerebral cortex is for unsupervised learning.This paper investigates how the learning modules specialized for these three kinds of learning can be assembled into goal-oriented behaving systems. In general, supervised learning modules in the cerebellum can be utilized as “internal models” of the environment. Reinforcement learning modules in the basal ganglia enable action selection by an “evaluation” of environmental states. Unsupervised learning modules in the cerebral cortex can provide statistically efficient representation of the states of the environment and the behaving system. Two basic action selection architectures are shown, namely, reactive action selection and predictive action selection. They can be implemented within the anatomical constraint of the network linking these structures. Furthermore, the use of the cerebellar supervised learning modules for state estimation, behavioral simulation, and encapsulation of learned skill is considered. Finally, the usefulness of such theoretical frameworks in interpreting brain imaging data is demonstrated in the paradigm of procedural learning.     

Importance of ‘inflammatory molecules’, but not necessarily of inflammation,in the pathophysiology of bipolar disorder and in the mechanisms of action of anti-bipolar drugs

It is often supposed that inflammation plays a major role in the pathophysiology of bipolar disorder and that reduction of inflammation by the classical anti-bipolar drugs, the lithium ion (lithium), carbamazepine and valproic acid, partly explain their therapeutic effect. The present mini-review summarizes data for enhanced expression in bipolar patients of ‘inflammatory molecules’, i.e., cytokines and metabolites of arachidonic acid (e.g., prostaglandins) and the enzymes (e.g., COX2) that catalyze this metabolism. However, it points out that enhanced transmitter activity during manic phases may play a major part in this upregulation. It also shows that chronic treatment with any of the 3 anti-bipolar drugs, known to decrease expression of the enzyme that releases arachidonic acid (cPLA₂) in whole brain, has this effect only in neurons, whereas it upregulates cPLA₂ expression in astrocytes. Literature data are presented that this upregulation may have therapeutically beneficial effects in bipolar disorder, supporting increasing evidence for involvement of not only neurons but also astrocytes in bipolar disorder and anti-bipolar drug action.     

Dose-related biphasic effect of the Parkinson’s disease neurotoxin MPTP,on the spread,accumulation, and toxicity of α-synuclein

BackgroundParkinson’s disease (PD), the second most common progressive neurodegenerative disorder, is characterized by the abnormal accumulation of intraneuronal inclusions enriched in aggregated α-synuclein (α-syn), known as Lewy bodies (LBs) and Lewy neurites (LNs), and significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the brain. Recent evidence suggests that the intrastriatal inoculation of α-syn preformed fibrils (PFF) in mice brain triggers endogenous α-syn in interconnected brain regions. 1-methyl, 4-phenyl, 1,2,3,6 tetrahydropyridine (MPTP), a mitochondrial neurotoxin, has been used previously to generate a PD mouse model. However, the common methods of MPTP exposure do not induce LB or α-syn aggregation in mice. In the present study, we evaluated the effect of different doses of MPTP (10 mg/kg.b.wt and/or 25 mg/kg.b.wt) on the spread, accumulation, and toxicity of endogenous α-syn in mice administered an intrastriatal injection of human α-syn PFF.MethodsWe inoculated human WT α-syn PFF in mouse striatum. At 6 weeks post PFF injection, we challenged the animal with two different doses of MPTP (10 mg/kg.b.wt and 25 mg/kg.b.wt) once daily for five consecutive days. At 2 weeks from the start of the MPTP regimen, we collected the mice brain and performed immunohistochemical analysis, and Rotarod test to assess motor coordination and muscle strength before and after MPTP injection.ResultsA single injection of human WT α-syn PFF in the mice striatum induced the propagation of α-syn, occurring as phosphorylated α-synuclein (pS129), towards the SNpc, within a very short time. Injection of a low dose of MPTP (10 mg/kg.b.wt) at 6 weeks post α-syn PFF inoculation further enhanced the spread, whereas a high dose of MPTP (25 mg/kg.b.wt.) reduced the spread. Majority of the accumulated α-syn were proteinase K resistant, as recognized using a conformation-specific α-syn antibody. Injection of α-syn PFF alone caused 12 % reduction in the number of tyrosine hydroxylase positive neurons while α-syn PFF + a low dose of MPTP caused 33 % reduction (loss), compared to the control mice injected with saline. This combination also reduced the motor coordination. Interestingly, a low dose of MPTP alone did not cause any significant reduction in the number of tyrosine hydroxylase positive neurons compared to saline treatment. Animals that received α-syn PFF and a high dose of MPTP showed massive activation of glial cells and decreased spread of α-syn, majority of which were detected in the nucleus.ConclusionOur results suggest that a combination of human WT α-syn PFF and a low dose of MPTP increases the pathological conversion and propagation of endogenous α-syn, and neurodegeneration, within a very short time. Our model can be used to study the mechanisms of α-syn propagation and screen for potential drugs against PD.