S100B protein, astrocytes and memory

S100 is a vertebrate-specific family of small, calcium-binding proteins. One of them is the S100B protein, mostly expressed in, and released by astroglial cells in the brain. The protein has been implicated in the regulation of numerous processes including phosphorylation of cytoskeletal proteins, cell proliferation and differentiation, as well as many other functions. This article focuses on the role of S100B in processes relating to learning and memory. More than four decades of behavioral and neurophysiological research have revealed beneficial effects of this protein. However, there is also evidence suggesting that overexpression of S100B can lead to memory dysfunction. It is possible that an increased S100B release from astrocytes may be co-responsible for memory dysfunction observed in the early stages of Alzheimer's disease

Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent

Substance use disorder is linked to impairments in the ventral tegmental area (VTA) dopamine (DA) reward system. Noradrenergic (NA) inputs from locus coeruleus (LC) into VTA have been shown to modulate VTA neuronal activity, and are implicated in psychostimulant effects. Phasic LC activity controls time- and context-sensitive processes: decision making, cognitive flexibility, motivation and attention. However, it is not yet known how such temporally-distinct LC activity contributes to cocaine seeking. In a previous study we demonstrated that pharmacological inhibition of NA signaling in VTA specifically attenuates cocaine-seeking. Here, we used virally-delivered opsins to target LC neurons for inhibition or excitation, delivered onto afferents in VTA of male rats seeking cocaine under extinction conditions. Optogenetic stimulation or inhibition was delivered in distinct conditions: upon active lever press, contingently with discreet cues; or non-contingently, i.e., throughout the cocaine seeking session. Non-contingent inhibition of LC noradrenergic under extinction conditions. In contrast, contingent inhibition increased, while contingent stimulation reduced cocaine seeking. These findings were specific for cocaine, but not natural reward (food) seeking. Our results show that NA release in VTA drives behavior depending on timing and contingency between stimuli – context, discreet conditioned cues and reinforcer availability. We show that, depending on those factors, noradrenergic signaling in VTA has opposing roles, either driving CS-induced drug seeking, or contributing to behavioral flexibility and thus extinction

Acute stress modulates noradrenergic signaling in the ventral tegmental area-amygdalar circuit

Noradrenergic neurotransmission is a critical mediator of stress responses. In turn, exposure to stress induces noradrenergic system adaptations, some of which are implicated in the etiology of stress-related disorders. Adrenergic receptors (AR) in the ventral tegmental area (VTA) have been demonstrated to regulate phasic dopamine (DA) release in the forebrain, necessary for behavioral responses to conditional cues. However, the impact of stress on noradrenergic modulation of the VTA has not been previously explored. We demonstrate that ARs in the VTA regulate dopaminergic activity in the VTA-BLA (basolateral amygdala) circuit, a key system for processing stress-related stimuli; and that such control is altered by acute stress. We utilized fast-scan cyclic voltammetry to assess the effects of intra-VTA microinfusion of α1 -AR and α2 -AR antagonists (terazosin and RX-821002, respectively), on electrically evoked phasic DA release in the BLA in stress-naïve and stressed (unavoidable electric shocks - UES) anaesthetized male Sprague-Dawley rats. In addition, we used western blotting to explore UES-induced alterations in AR protein level in the VTA. Intra-VTA terazosin or RX-821002 dose-dependently attenuated DA release in the BLA. Interestingly, UES decreased the effects of intra-VTA α2 -AR blockade on DA release (24 h but not 7 days after stress), while the effects of terazosin were unchanged. Despite changes in α2 -AR physiological function in the VTA, UES did not alter α2 -AR protein levels in either intracellular or membrane fractions. These findings demonstrate that NA-ergic modulation of the VTA-BLA circuit undergoes significant alterations in response to acute stress, with α2 -AR signaling indicated as a key target

Alpha1_{1}-adrenergic receptor blockade in the ventral tegmental area attenuates acquisition of cocaine-induced pavlovian associative learning

Activity of the alpha1-adrenergic receptor (α1-AR) in the ventral tegmental area (VTA) modulates dopaminergic activity, implying its modulatory role in the behavioral functions of the dopamine (DA) system. Indeed, intra-VTA α1-AR blockade attenuates conditioned stimulus dependent behaviors such as drug seeking responses signifying a role of the noradrenergic signaling in the VTA in conditioned behaviors. Importantly, the role of the VTA α1-AR activity in Pavlovian associative learning with positive outcomes remains unknown. Here, we aimed to examine how intra-VTA α1-AR blockade affects acquisition of cocaine-induced Pavlovian associative learning in the conditioned place preference (CPP) paradigm. The impact of α1-AR blockade on cocainereinforced operant responding and cocaine-evoked ultrasonic vocalizations (USVs) was also studied. In addition, both α1-AR immunoreactivity in the VTA and its role in phasic DA release in the nucleus accumbens (NAc) were assessed. We demonstrated cellular localization of α1-AR expression in the VTA, providing a neuroanatomical substrate for the α1-AR echanism. We showed that prazosin (α1-AR selective antagonist; 1 µg/0.5 µl) microinfusion attenuated electrically evoked DA transients in the NAc and dose-dependently (0.1–1 µg/0.5 µl) prevented the acquisition of cocaine CPP but did not affect cocaine-reinforced operant responding nor cocaine-induced positive affective state (measured as USVs). We propose that the VTA α1-AR signaling is necessary for the acquisition of Pavlovian associative learning but does not encode hedonic value. Thus, α1-AR signaling in the VTA might underlie salience encoding of environmental stimuli and reflect an ability of erting/orienting functions, originating from bottom-up information processing to guide behaviors

S100 protein, astrocytes, and memory

S100 to występująca u kręgowców rodzina małych, wiążących wapń białek. Jednym z nich jest S100B, białko występujące głównie w astrocytach. Komórki te są również źródłem S100B uwalnianego do przestrzeni międzykomórkowej. Białko S100B uczestniczy w regulacji wielu procesów, takich jak: fosforylacja białek cytoszkieletowych, namnażanie się i różnicowanie komórek. Prowadzone od ponad 40 lat badania dowodzą, że S100B ma dodatni wpływ na procesy uczenia się. Są jednak również dowody wskazujące na to, że nadmiar S100B może prowadzić do zaburzeń pamięci. Jest możliwe, że zwiększone wydzielanie S100B przez astrocyty może być współodpowiedzialne za deficyty pamięci obserwowane we wczesnych stadiach choroby Alzheimera

Structural changes in the neocortex as correlates of variations in EEG spectra and seizure susceptibility in rat brains with different degrees of dysplasia

Disturbances of the early stages of neurogenesis lead to irreversible changes in the structure of the mature brain and its functional impairment, including increased excitability, which may be the basis for drug-resistant epilepsy. The range of possible clinical symptoms is as wide as the different stages of disturbed neurogenesis may be. In this study, we used a quadruple model of brain dysplasia by comparing structural and functional disorders in animals whose neurogenesis was disturbed with a single dose of 1 Gy of gamma rays at one of the four stages of neurogenesis, that is, on days 13, 15, 17, or 19 of prenatal development. When reached adulthood, the prenatally irradiated rats received EEG teletransmitter implantation. Thereafter, pilocarpine was administered and significant differences in susceptibility to seizure behavioral symptoms were detected depending on the degree of brain dysplasia. Before, during, and after the seizures significant correlations were found between the density of parvalbumin-immunopositive neurons located in the cerebral cortex and the intensity of behavioral seizure symptoms or increases in the power of particular EEG bands. Neurons expressing calretinin or NPY showed also dysplasia-related increases without, however, correlations with parameters of seizure intensity. The results point to significant roles of parvalbumin-expressing interneurons, and also to expression of NPY-an endogenous anticonvulsant and neuroprotectant reducing susceptibility to seizures and supporting neuronal survival

Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling.

Phasic dopamine (DA) release from the ventral tegmental area(VTA) into forebrain structures is implicated in associativelearning and conditional stimulus (CS)-evoked behavioralresponses. Mounting evidence points to noradrenaline signal-ing in the VTA as an important regulatory input. Accordingly,adrenergic receptor (AR) blockade in the VTA has beenshown to modulate CS-dependent behaviors. Here, wehypothesized thata1- anda2-AR (but notb-AR) activitypreferentially modulates phasic, in contrast to tonic, DArelease. In addition, these effects could differ betweenforebrain targets. We used fast-scan cyclic voltammetricmeasurements in rats to assess the effects of intra-VTAmicroinfusion of terazosin, a selectivea1-AR antagonist, onelectrically evoked phasic DA release in the nucleus accum-bens (NAc) core and medial prefrontal cortex (mPFC).Terazosin dose-dependently attenuated phasic, but not tonic,DA release in the NAc core, but not in the mPFC. Next, we measured the effects of intra-VTA administration of thea2-ARselective antagonist RX-821002 on evoked DA in the NAccore. Similar to the effects ofa1-AR blockade, intra-VTAa2-ARblockade with RX-0821002 strongly and dose-dependentlyattenuated phasic, but not tonic, DA release. In contrast, noregulation by RX-821002 was observed in the mPFC. Thiseffect was sensitive to intra-VTA blockade of D2 receptors withraclopride. Finally, theb-AR antagonist propranolol ineffec-tively modulated DA release in the NAc core. Thesefindingsrevealed botha1- anda2-ARs in the VTA as selectiveregulators of phasic DA release. Importantly, we demonstratedthat AR blockade modulated mesolimbic, in contrast tomesocortical, DA release in previously unstudied heterogene-ity in AR regulation of forebrain phasic DA