Anna Mattsson

Nogo receptor 1 regulates formation of lasting memories

Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now show that mice with inducible overexpression of NgR1 in forebrain neurons have normal long-term potentiation and normal 24-h memory, but severely impaired month-long memory in both passive avoidance and swim maze tests. Blocking transgene expression normalizes these memory impairments. Nogo, Lingo-1, Troy, endogenous NgR1, and BDNF mRNA expression levels were not altered by transgene expression, suggesting that the impaired ability to form lasting memories is directly coupled to inability to down-regulate NgR1. Regulation of NgR1 may therefore serve as a key regulator of memory consolidation. Understanding the molecular underpinnings of synaptic rearrangements that carry lasting memories may facilitate development of treatments for memory dysfunction.

Facilitation of Dopamine-Mediated Locomotor Activity in Adult Rats following Cholinergic Denervation

The dopamine hypothesis of schizophrenia postulates hyperactivity of dopaminergic neurotransmission in the mesolimbic system. However, the possible underlying causes for this dopaminergic overfunction are not well understood. Therefore, the main aim of this study was to examine the effect of central cholinergic denervation on dopamine-mediated functions. We also examined the effect of neonatal cholinergic denervation upon adult brain function. The immunotoxin 192 IgG-saporin causes severe lesions of the basal forebrain cholinergic system when infused into the lateral ventricles by targeting neurons expressing the p75 neurotrophin receptor. The toxin may also damage p75-expressing Purkinje neurons in the cerebellum. We have compared the behavioral effects of intracerebroventricular injections of 192 IgG-saporin to adult rats with that of injections to neonate rats. As expected, adult treated rats displayed an almost complete cholinergic denervation of forebrain corticohippocampal areas concomitant with a marked impairment in the Morris water maze. When tested as adults, neonatally treated animals had a less complete cholinergic denervation and showed lesser impairments in water maze behaviors. Interestingly, adult treated rats showed increased spontaneous horizontal activity and a remarkable increase in locomotor response to d-amphetamine as evidenced by increased horizontal and vertical activity. There were no marked changes of spontaneous or drug-induced locomotor activity in adult rats treated with 192 IgG-saporin as neonates. These results suggest that cholinergic denervation of the forebrain causes a marked enhancement of behavioral responses related to dopaminergic activity, probably mainly mediated presynaptically. However, it cannot be fully excluded that damage to noncholinergic systems, e.g., Purkinje cells, might contribute to the effects. The striking overreaction to dopaminergic stimuli, presumably caused by the cholinergic deficit, is discussed in relation to the suggested role of cholinergic malfunctioning in schizophrenia.

HOMA‐IR and QUICKI: decide on a general standard instead of making further comparisons

Aim:  To limit further comparisons between the two fasting indices Homeostasis Model Assessment for Insulin Resistance (HOMA‐IR) and Quantitative Insulin Sensitivity Check Index (QUICKI), and to examine their robustness in assessing insulin sensitivity.

Loss of cortical acetylcholine enhances amphetamine-induced locomotor activity.

Cholinergic disturbances have been implicated in schizophrenia. In a recent study we found that intracerebroventricular (i.c.v.) delivery of the immunotoxin 192 IgG-saporin, that effectively destroys cholinergic projections from the basal forebrain to hippocampus and cortex cerebri, leads to a marked facilitation of amphetamine-induced locomotor activity in adult rats. The aim of the present experiments was to evaluate the contribution of the septohippocampal versus the basalocortical cholinergic projections for the amphetamine hyper-response seen previously in i.c.v. 192 IgG-saporin injected rats. Since i.c.v. delivery of 192 IgG-saporin also destroys a population of Purkinje neurons in cerebellum, this cell loss needs to be taken into consideration as well. Cortex cerebri and hippocampus were selectively cholinergically denervated by intraparenchymal injections of 192 IgG-saporin into nucleus basalis magnocellularis and the medial septum/diagonal band of Broca, respectively. Selective loss of Purkinje cells in cerebellum was achieved by i.c.v. delivery of OX7 saporin. Possible effects of these three lesions on spontaneous and amphetamine-induced locomotor activity were assessed in locomotor activity cages. We find that selective cholinergic denervation of cortex cerebri, but not denervation of hippocampus or damage to cerebellum can elicit dopaminergic hyper-reactivity similar to that seen in previous i.c.v. 192 IgG-saporin experiments. Our data are compatible with the hypothesis that disturbances of cholinergic neurotransmission in cortex cerebri may be causally involved in forms of schizophrenia.

Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation

Dysregulated cholinergic neurotransmission has been implicated in the pathophysiology of schizophrenia, particularly negative symptoms and cognitive deficits. The aim of the present study was to evaluate the role of neocortical cholinergic innervation and of the N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP) on social interaction and novel object recognition (NOR), a declarative memory task. The cholinergic corticopetal projection was lesioned by local infusion of the immunotoxin 192 IgG-saporin into nucleus basalis magnocellularis of adult male Lister hooded rats. Behavior was assessed 2.5 weeks later in a social interaction paradigm followed by the NOR task. We found that selective cholinergic denervation of neocortex led to a significant reduction in duration of social interaction, specifically active social interaction. Acute administration of PCP (1.0 mg/kg, s.c.) caused a marked decrease of active social interaction, such that there was no longer a difference between intact and denervated animals. Neither cholinergic denervation alone, nor PCP (1.0 mg/kg, s.c.) alone blocked the ability of rats to recognize a novel object. However, when animals lacking cortical cholinergic innervation were challenged by PCP, they were no longer able to recognize a novel object. This study indicates that rats lacking cholinergic innervation of neocortex have impaired social interaction and specifically that the duration of active contact is shortened. Animals with severe cortical cholinergic hypofunction maintain the ability to perform in a declarative memory test, although the task is carried out less intensively. However, a provocation of psychosis-like behavior by a dose of PCP that does not by itself impair performance in normal animals, will abolish the ability to recognize novel objects in animals lacking cortical cholinergic innervation. The present findings support a possible role for cortical cholinergic hypofunction in the negative and cognitive symptoms of schizophrenia, and the potential for cholinergic augmentation as part of the pharmacological profile of antipsychotic drugs.

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.

NgR1: A Tunable Sensor Regulating Memory Formation, Synaptic, and Dendritic Plasticity

Nogo receptor 1 (NgR1) is expressed in forebrain neurons and mediates nerve growth inhibition in response to Nogo and other ligands. Neuronal activity downregulates NgR1 and the inability to downregulate NgR1 impairs long-term memory. We investigated behavior in a serial behavioral paradigm in mice that overexpress or lack NgR1, finding impaired locomotor behavior and recognition memory in mice lacking NgR1 and impaired sequential spatial learning in NgR1 overexpressing mice. We also investigated a role for NgR1 in drug-mediated sensitization and found that repeated cocaine exposure caused stronger locomotor responses but limited development of stereotypies in NgR1 overexpressing mice. This suggests that NgR1-regulated synaptic plasticity is needed to develop stereotypies. Ex vivo magnetic resonance imaging and diffusion tensor imaging analyses of NgR1 overexpressing brains did not reveal any major alterations. NgR1 overexpression resulted in significantly reduced density of mature spines and dendritic complexity. NgR1 overexpression also altered cocaine-induced effects on spine plasticity. Our results show that NgR1 is a negative regulator of both structural synaptic plasticity and dendritic complexity in a brain region-specific manner, and highlight anterior cingulate cortex as a key area for memory-related plasticity.

Hippocampal Morphology in a Rat Model of Depression: The Effects of Physical Activity

Accumulating in vivo and ex vivo evidences show that humans suffering from depression have decreased hippocampal volume and altered spine density. Moreover, physical activity has an antidepressant effect in humans and in animal models, but to what extent physical activity can affect hippocampal volume and spine numbers in a model for depression is not known. In this study we analyzed whether physical activity affects hippocampal volume and spine density by analyzing a rodent genetic model of depression, Flinders Sensitive Line Rats (FSL), with Magnetic Resonance Imaging (MRI) and ex vivo Golgi staining. We found that physical activity in the form of voluntary wheel running during 5 weeks increased hippocampal volume. Moreover, runners also had larger numbers of thin spines in the dentate gyrus. Our findings support that voluntary wheel running, which is antidepressive in FSL rats, is associated with increased hippocampal volume and spine numbers.

Cholinergic denervation attenuates phencyclidine-induced c-fos responses in rat cortical neurons.

The cortical cholinergic innervation, which is important for memory and cognition, has been implicated in schizophrenia. To experimentally analyze such a possible role of the cholinergic system, we have used the dissociative drug phencyclidine (PCP), known to produce schizophrenia-like psychosis in humans, to model aspects of schizophrenia in rats. We previously showed that induced cortical cholinergic hypofunction leads to enhanced PCP-induced locomotor activity and attenuated social interaction. After PCP, rats lacking cortical cholinergic innervation also show impaired declarative memory. To directly study the role of the basalo-cortical cholinergic projections for PCP-induced neural activation in different cortical areas, we have now monitored the rapid (30 and 60 min) effects of low doses of PCP (2 and 3mg/kg) on neural activation as reflected by transcriptional activation of c-fos in cortical areas, using quantitative in situ hybridization. We find an almost pan-cortical neural induction of c-fos mRNA with doses of PCP low enough not to alter levels of either BDNF or Nogo receptor mRNA levels. Specific unilateral lesioning of the uncrossed cholinergic projections to the cortical mantle by 192-IgG-saporin immunotoxin delivery to nc basalis (NBM) caused a striking ipsilateral decrease of the PCP-induced cortical c-fos mRNA induction, restricted to areas which had become effectively denervated. Because PCP at low doses is unlikely to directly influence cortical neurons, we suggest that it acts by activation of the cholinergic input, which in turn leads to cortical c-fos mRNA increases. Our results are compatible with a role for the cholinergic system in symptoms of schizophrenia, by showing that the basalo-cortical cholinergic projections are needed in order for PCP to have full activating effects on cortical neurons.