rudyvdbrink/CitationDatabase huggingface dataset:
Persistent peripheral inflammation attenuates morphine-induced periaqueductal gray glial cell activation and analgesic tolerance in the male rat.
The journal of pain, 2013

Morphine is among the most prevalent analgesics prescribed for chronic pain. However, prolonged morphine treatment results in the development of analgesic tolerance. An abundance of evidence has accumulated indicating that central nervous system glial cell activity facilitates pain transmission and opposes morphine analgesia. While the midbrain ventrolateral periaqueductal gray (vlPAG) is an important neural substrate mediating pain modulation and the development of morphine tolerance, no studies have directly assessed the role of PAG glia. Here we test the hypothesis that morphine-induced increases in vlPAG glial cell activity contribute to the development of morphine tolerance. As morphine is primarily consumed for the alleviation of severe pain, the influence of persistent inflammatory pain was also assessed. Administration of morphine, in the absence of persistent inflammatory pain, resulted in the rapid development of morphine tolerance and was accompanied by a significant increase in vlPAG glial activation. In contrast, persistent inflammatory hyperalgesia, induced by intraplantar administration of complete Freund's adjuvant (CFA), significantly attenuated the development of morphine tolerance. No significant differences were noted in vlPAG glial cell activation for CFA-treated animals versus controls. These results indicate that vlPAG glia are modulated by a persistent pain state, and implicate vlPAG glial cells as possible regulators of morphine tolerance.
The basolateral nucleus of the amygdala is necessary to induce the opposing effects of stressful experience on learning in males and females.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008

The basolateral nucleus of the amygdala (BLA) has been implicated in the modulation of learning after stress. Acute inescapable stress enhances classical eyeblink conditioning in male rats, whereas the same stressor impairs eyeblink conditioning in female rats. The experiments here directly assessed whether inactivation of the BLA during stress exposure would block both the stress-induced facilitation in males and the retardation of eyeblink conditioning in females. To this end, the BLA was temporarily inactivated by infusion of the GABA agonist muscimol before acute stressor exposure. All rats were trained in a different context 24 h later. Males infused with muscimol before the stressful event did not exhibit facilitated eyeblink conditioning, whereas those infused with the vehicle emitted more conditioned responses than unstressed males. Females infused with muscimol before stress did not express a deficit in conditioning, whereas those infused with vehicle and stressed emitted fewer conditioned responses than unstressed vehicle controls. These data demonstrate that neuronal activity within the BLA during stress exposure is necessary to modulate learning 24 h later in a new context. Thus, the BLA is necessary to induce the long-term effect of stressful experience on conditioning regardless of sex and direction of modulation.
Human memory development and its dysfunction after early hippocampal injury.
Trends in neurosciences, 2006

Cognitive memory involves long-term memories for facts (semantic memory) and personal experiences (episodic memory) that can be brought to mind. There is consensus that the hippocampus and related medial temporal lobe (MTL) structures are crucial for adult cognitive memory, but much less is known about their contribution to memory during infancy and childhood. We argue that the MTL is involved in memory from early in life, supporting recognition memory within the first postnatal months and recall memory within the first year. We propose that normal development involves a sequence in which a form of semantic-like memory emerges first, whereas the characteristics of episodic memory develop only later with progressive development of the hippocampus. Early bilateral injury to the hippocampus disrupts this normal pattern such that memory skills cannot develop beyond the stage of semantic memories. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).
Accuracy of three activity monitors in patients with chronic obstructive pulmonary disease: a comparison with video recordings.
COPD, 2014

Low physical activity and sedentary behaviour characterise the lives of patients with chronic obstructive pulmonary disease (COPD). Using activity monitors, assessment of both aspects are possible, but many outcomes are not well validated. The aim of this study was to assess the accuracy and equivalency of three activity monitors regarding steps, body position and their ability to differentiate between periods of physical activity and inactivity. Fifteen patients with COPD (8 females; median (interquartile range, IQR) age, 64 (59-69) years; forced expiratory volume in 1 second, 37 (28-48)% predicted; 6-minute walk distance, 444 (410-519) m) were enrolled. The DynaPort ADL-monitor, the DynaPort MiniMod monitor and the SenseWear Armband Pro 3 monitor were assessed. Subjects performed a structured protocol alternating physical activity and inactivity while simultaneously wearing all three monitors and being video recorded. The mean difference (limits of agreement) in step count from monitors compared to manual step count was -69 (-443 to 305) for the ADL-monitor, -19 (-141 to 103) for the MiniMod and -479 (-855 to -103) for the SenseWear Armband. Compared to the video, the sitting time was 97 (94-100)% when measured by the ADL-monitor and 121 (110-139)% by the MiniMod. Standing time was 114 (107-122)% when measured by the ADL-monitor and 68 (47-106)% by the MiniMod. Activity monitors are not equivalent in their abilities to detect steps or body positions. The choice of monitor should be based on the particular outcome of interest.
Opposite actions of alcohol on tonic GABA(A) receptor currents mediated by nNOS and PKC activity.
Nature neuroscience, 2013

The molecular mechanisms that mediate genetic variability in response to alcohol are unclear. We found that alcohol had opposite actions (enhancement or suppression) on GABA(A) receptor (GABA(A)R) inhibition in granule cells from the cerebellum of behaviorally sensitive, low alcohol-consuming Sprague-Dawley rats and DBA/2 mice and behaviorally insensitive, high alcohol-consuming C57BL/6 mice, respectively. The effect of alcohol on granule cell GABA(A)R inhibition was determined by a balance between two opposing effects: enhanced presynaptic vesicular release of GABA via alcohol inhibition of nitric oxide synthase (NOS) and a direct suppression of the activity of postsynaptic GABA(A)Rs. The balance of these two processes was determined by differential expression of neuronal NOS (nNOS) and postsynaptic PKC activity, both of which varied across the rodent genotypes. These findings identify opposing molecular processes that differentially control the magnitude and polarity of GABA(A)R responses to alcohol across rodent genotypes.
Tuning of delta-protocadherin adhesion through combinatorial diversity.
eLife, 2018

The delta-protocadherins (δ-Pcdhs) play key roles in neural development, and expression studies suggest they are expressed in combination within neurons. The extent of this combinatorial diversity, and how these combinations influence cell adhesion, is poorly understood. We show that individual mouse olfactory sensory neurons express 0-7 δ-Pcdhs. Despite this apparent combinatorial complexity, K562 cell aggregation assays revealed simple principles that mediate tuning of δ-Pcdh adhesion. Cells can vary the number of δ-Pcdhs expressed, the level of surface expression, and which δ-Pcdhs are expressed, as different members possess distinct apparent adhesive affinities. These principles contrast with those identified previously for the clustered protocadherins (cPcdhs), where the particular combination of cPcdhs expressed does not appear to be a critical factor. Despite these differences, we show δ-Pcdhs can modify cPcdh adhesion. Our studies show how intra- and interfamily interactions can greatly amplify the impact of this small subfamily on neuronal function.
Beyond slots and resources: grounding cognitive concepts in neural dynamics.
Attention, perception & psychophysics, 2014

Research over the past decade has suggested that the ability to hold information in visual working memory (VWM) may be limited to as few as three to four items. However, the precise nature and source of these capacity limits remains hotly debated. Most commonly, capacity limits have been inferred from studies of visual change detection, in which performance declines systematically as a function of the number of items that participants must remember. According to one view, such declines indicate that a limited number of fixed-resolution representations are held in independent memory "slots." Another view suggests that such capacity limits are more apparent than real, but emerge as limited memory resources are distributed across more to-be-remembered items. Here we argue that, although both perspectives have merit and have generated and explained impressive amounts of empirical data, their central focus on the representations--rather than processes--underlying VWM may ultimately limit continuing progress in this area. As an alternative, we describe a neurally grounded, process-based approach to VWM: the dynamic field theory. Simulations demonstrate that this model can account for key aspects of behavioral performance in change detection, in addition to generating novel behavioral predictions that have been confirmed experimentally. Furthermore, we describe extensions of the model to recall tasks, the integration of visual features, cognitive development, individual differences, and functional imaging studies of VWM. We conclude by discussing the importance of grounding psychological concepts in neural dynamics, as a first step toward understanding the link between brain and behavior.
Effects of sympathectomy on a rat model of peripheral neuropathy.
Pain, 1993

The aim of this study was to determine the effects of sympathectomy on our previously developed animal model for neuropathic pain. The neuropathy was produced by a unilateral tight ligation of the L5 and L6 spinal nerves in 81 rats, all of which showed a marked increase in frequency of paw lifting in response to innocuous mechanical stimuli and a shortened latency of paw withdrawal in response to noxious radiant heat stimuli on the affected limb. We interpreted these as behavioral signs of mechanical allodynia and heat hyperalgesia. Surgical sympathectomy was performed by removing the sympathetic chain bilaterally from the L2 to L6 levels at 1 week prior to and 1, 3 and 5 weeks after nerve injury. In addition, the effect of sympathetic block was tested by systemically injecting guanethidine or phentolamine. Surgical sympathectomy relieved the signs of both mechanical allodynia and heat hyperalgesia. The effect of sympathectomy for mechanical allodynia is estimated to be almost fully expressed within 30 min after the operation. Sympathetic block by chemical agents reversibly relieved the mechanical allodynia. These data suggest that the rats in our model exhibit behavioral signs of neuropathic pain that are sympathetically maintained.
Membrane progestin receptors in the midbrain ventral tegmental area are required for progesterone-facilitated lordosis of rats.
Hormones and behavior, 2013

Progesterone (P₄) and its metabolites, rapidly facilitate lordosis of rats partly through actions in the ventral tegmental area (VTA). The study of membrane progestin receptors (mPRs), of the Progestin and AdipoQ Receptor (PAQR) superfamily, has been limited to expression and regulation, instead of function. We hypothesized that if mPRs are required for progestin-facilitated lordosis in the VTA, then mPRs will be expressed in this region and knockdown will attenuate lordosis. First, expression of mPR was examined by reverse-transcriptase polymerase chain reaction (RT-PCR) in brain and peripheral tissues of proestrous Long-Evans rats. Expression of mPRα (paqr7) was observed in peripheral tissues and brain areas, including hypothalamus and midbrain. Expression of mPRβ (paqr8) was observed in brain tissues and was abundant in the midbrain and hypothalamus. Second, ovariectomized rats were estrogen (E₂; 0.09 mg/kg, SC), and P₄ (4 mg/kg, SC) or vehicle-primed, and infused with antisense oligodeoxynucleotides (AS-ODNs) targeted against mPRα and/or mPRβ intracerebroventricularly or to the VTA. Rats were assessed for motor (open field), anxiety (elevated plus maze), social (social interaction), and sexual (lordosis) behavior. P₄-facilitated lordosis was significantly reduced with administration of AS-ODNs for mPRα, mPRβ, or co-administration of mPRα and mPRβ to the lateral ventricle, compared to vehicle. P₄-facilitated lordosis was reduced, compared to vehicle, by administration of mPRβ AS-ODNs, or co-administration of mPRα and mPRβ AS-ODNs, but not mPRα AS-ODNs alone, to the VTA. No differences were observed for motor, anxiety, or social behaviors. Thus, mPRs in the VTA are targets of progestin-facilitated lordosis of rats.
Chronic stress in adolescence differentially affects cocaine vulnerability in adulthood in a selectively bred rat model of individual differences: role of accumbal dopamine signaling.
Stress (Amsterdam, Netherlands), 2021

Stress during adolescence has profound effects on the onset and severity of substance use later in life. However, not everyone with adverse experiences during this period will go on to develop a substance use disorder in adulthood, and the factors that alter susceptibility to substance use remain unknown. Here, we investigated individual differences in response to stress and drugs of abuse using our selectively bred high-responder (bHR) and low-responder (bLR) rats. These animals model extremes of temperamental tendencies and differ dramatically in both stress responsiveness and addiction-related traits. The present study investigated how environmental interventions in the form of a chronic variable stress (CVS) regimen in early adolescence interact with the bHR/bLR phenotype to alter behavioral sensitization to cocaine in adulthood. We also determined whether accumbal dopamine signaling is involved in the interaction of stress history and cocaine by assessing the mRNA levels of dopamine D1 (D1R) and D2 (D2R) receptors. Our results showed that CVS history alone had enduring and phenotype-specific effects on accumbal dopamine signaling. Importantly, adolescent stress had opposing effects in the two lines- decreasing the locomotor response to cocaine challenge in bHRs but increasing this measure in bLRs. Moreover, these opposing effects on cocaine sensitivity following adolescent CVS were accompanied by parallel effects in the accumbal dopamine system, with prior stress and cocaine exposure interacting to decrease D2R mRNA in bHRs but increase it in bLRs. Overall, these findings indicate that environmental challenges encountered in adolescence interact with genetic background to alter vulnerability to cocaine later in life.Lay SummaryStress experienced during adolescence affects the onset and severity of drug dependence later in life. However, not everyone with adverse experiences during this period will go on to develop SUD in adulthood. Using a rat model of innate differences in emotional reactivity, this study shows that the interplay between individual temperament and previous experience of adolescent stress/trauma determines whether an individual will be vulnerable or resilient to develop SUDs later in life. In addition, the present study shows that the dopamine D2 receptor in the brain's reward center, nucleus accumbens, may be implicated in this interplay.
Serotonin depletion in the dorsal and ventral hippocampus: effects on locomotor hyperactivity, prepulse inhibition and learning and memory.
Neuropharmacology, 2008

We present an overview of our studies on the differential role of serotonergic projections from the median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) in behavioural animal models with relevance to schizophrenia. Stereotaxic microinjection of the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the MRN or one of its main projections regions, the dorsal hippocampus, induced a marked enhancement of phencyclidine-induced locomotor hyperactivity and a disruption of prepulse inhibition (PPI) in rats. There was no enhancement of locomotor hyperactivity induced by amphetamine or MK-801 or after 5,7-DHT lesions of the DRN or ventral hippocampus. Rats with dorsal hippocampus lesions did not show significant changes in the Y-maze test for short-term spatial memory, the Morris water maze for long-term spatial memory, or in the T-maze delayed alternation test for working memory. These chronic lesion studies suggest a modulatory influence of serotonergic projections from the MRN to the dorsal hippocampus on phencyclidine effects and prepulse inhibition, but not on different forms of learning and memory. The results provide new insight into the role of serotonin in the dorsal hippocampus in aspects of schizophrenia.
Hemispherotomy in Rasmussen encephalitis: long-term outcome in an Italian series of 16 patients.
Epilepsy research, 2014

Surgical disconnection of the affected hemisphere is considered the treatment of choice for Rasmussen encephalitis (RE), however few data on long-term outcomes after disconnective surgery are available. We report on long-term seizure, cognitive and motor outcomes after disconnective surgery in 16 (8 M, 8 F) RE patients. Pre- and post-operative evaluations included long-term video-EEG monitoring, MRI, assessment of motor function, and cognitive evaluation. Hemispherotomy, by various techniques was used to obtain functional disconnection of the affected hemisphere. The patients, of median current age 23.5 years, range 12-33, were operated on between 1993 and 2009. Median age at disease onset was 5.8 years (range 3-11.4). Median time from seizure onset to surgery was 3.8 years, range 8 months to 21 years. Post-surgical follow-up was a median of 9.5 years, range 3-20. At surgery all patients were receiving two or more antiepileptic drugs (AEDs). All but three patients were seizure-free at latest follow-up. AEDs had been stopped in ten patients; in the remaining six AEDs were markedly reduced. Postural control improved in all patients. Gain in cognitive functioning was significantly (p=0.002) related to disease duration. The long-term outcomes, in terms of seizure control, motor improvement, and cognitive improvement provide important support for disconnective surgery as first choice treatment for RE.
Prenatal ethanol exposure stimulates neurogenesis in hypothalamic and limbic peptide systems: possible mechanism for offspring ethanol overconsumption.
Neuroscience, 2012

Exposure to ethanol during the prenatal period contributes to increased alcohol consumption and preference in rodents and increased risk for alcoholism in humans. With studies in adult animals showing the orexigenic peptides, enkephalin (ENK), galanin (GAL) and orexin (OX), to stimulate ethanol consumption, the question addressed here is whether prenatal ethanol alters the development in utero of specific neurons that express these peptides. With reports describing suppressive effects of high doses of ethanol, we examined the offspring of dams gavaged from embryonic day 9 to parturition with a control solution or lower ethanol doses, 1 and 3g/kg/day, known to promote ethanol consumption in the offspring. To understand underlying mechanisms, measurements were taken in postnatal offspring of the expression of ENK in the hypothalamic paraventricular nucleus (PVN) and nucleus accumbens (NAc), GAL in the PVN, and OX in the perifornical lateral hypothalamus (PFLH) using real-time qPCR and in situ hybridization, and also of the cell proliferation marker, 5-bromo-2-deoxyuridine (BrdU), and its double-labeling with either neuronal nuclei (NeuN), a marker of mature neurons, or the peptides. On postnatal day 15 (P15), after two weeks without ethanol, the offspring showed increased expression of ENK in the PVN and NAc core but not shell, GAL in the PVN, and OX in the PFLH. In these same areas, prenatal ethanol compared to control increased the density at birth (P0) of neurons expressing these peptides and at P0 and P15 of neurons double-labeling BrdU and NeuN, indicating increased neurogenesis. These BrdU-positive neurons were found to express ENK, GAL and OX, indicating that prenatal ethanol promotes neurogenesis in these specific peptide systems. There were no changes in gliogenesis or apoptosis. This increase in neurogenesis and density of peptide-expressing neurons suggests the involvement of these hypothalamic and accumbal peptide systems in mediating the increased alcohol consumption observed in prenatal ethanol-exposed offspring.
Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors.
Brain research, 2013

The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6×129×CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIα-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice (Boyle et al. 2005), and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action.