Chronic nicotine attenuates behavioral and synaptic plasticity impairments in a streptozotocin model of Alzheimer's disease.

Brain glucose metabolism is altered in sporadic Alzheimer's disease (sAD), whose pathologies are reproduced in rodents by intracerebroventricular (icv) infusion of streptozotocin (STZ) in subdiabetogenic doses. The icv-STZ model also culminates in central cholinergic dysfunctions, which in turn are known to underlie both the sAD cognitive decline, and synaptic plasticity impairments. Considering the cognitive-enhancing potential of chronic nicotine (Nic), we investigated whether it attenuates icv-STZ-induced impairments in recognition memory and synaptic plasticity in a cognition-relevant substrate: the hippocampal CA1-medial prefrontal cortex (mPFC) pathway. Rats treated with icv-STZ were submitted to a chronic Nic regime, and were evaluated for recognition memory. We then examined long-term potentiation (LTP), paired-pulse facilitation (PPF) under urethane anesthesia, and brains were also evaluated for hippocampus-mPFC cell density. We found that Nic treatment prevents icv-STZ-induced disruptions in recognition memory and LTP. STZ did not precipitate neuronal death, while Nic alone was associated with higher neuronal density in CA1 when compared to vehicle-injected animals. Through combining behavioral, neurophysiological, and neuropathological observations into the Nic-STZ interplay, our study reinforces that cholinergic treatments are of clinical importance against early-stage Alzheimer's disease and mild cognitive impairments.

The histamine H3 receptor antagonist thioperamide rescues circadian rhythm and memory function in experimental parkinsonism.

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by motor impairment and a wide range of non-motor symptoms, including sleep disorders and cognitive and affective deficits. In this study, we used a mouse model of PD based on 6-hydroxydopamine (6-OHDA) to examine the effect of thioperamide, a histamine H3 receptor antagonist, on circadian activity, recognition memory and anxiety. A partial, bilateral 6-OHDA lesion of the striatum reduces motor activity during the active phase of the 24 h cycle. In addition, the lesion disrupts the endogenous circadian rhythm observed when mice are maintained in constant darkness. Administration of thioperamide to 6-OHDA-lesion mice rescues the normal rest/activity cycle. Moreover, thioperamide counteracts the deficit of novel object recognition produced by 6-OHDA. Our experiments show that this memory impairment is accompanied by disrupted gamma oscillations in the hippocampus, which are also rescued by thioperamide. In contrast, we do not observe any modification of the anxiogenic effect of 6-OHDA in response to administration of thioperamide. Our results indicate that thioperamide may act as a multifunctional drug, able to counteract disruptions of circadian rhythm and cognitive deficits associated with PD.

The frequency of spontaneous seizures in rats correlates with alterations in sensorimotor gating, spatial working memory, and parvalbumin expression throughout limbic regions.

Cognitive deficits and psychotic symptoms are highly prevalent in patients with temporal lobe epilepsy (TLE). Imaging studies in humans have suggested that these comorbidities are associated with atrophy in temporal lobe structures and other limbic regions. It remains to be clarified whether TLE comorbidities are due to the frequency of spontaneous seizures or to limbic structural damage per se. Here, we used the pilocarpine model of chronic spontaneous seizures to evaluate the possible association of seizure frequency with sensorimotor gating, spatial working memory, and neuropathology throughout limbic regions. For TLE modeling, we induced a 2-h status epilepticus by the systemic administration of lithium-pilocarpine. Once spontaneous seizures were established, we tested the locomotor activity (open field), spatial working memory (eight-arm radial maze), and sensorimotor gating (prepulse inhibition of acoustic startle). After behavioral testing, the brains were sectioned for hematoxylin-eosin staining (cell density) and parvalbumin immunohistochemistry (GABAergic neuropil) in the prefrontal cortex, nucleus accumbens, thalamus, amygdala, hippocampus, and entorhinal cortex. The animal groups analyzed included chronic epileptic rats, their controls, and rats that received lithium-pilocarpine but eventually failed to express status epilepticus or spontaneous seizures. Epileptic rats showed deficits in sensorimotor gating that negatively correlated with the radial maze performance, and impairments in both behavioral tests correlated with seizure frequency. In addition to neuronal loss at several sites, we found increased parvalbumin immunostaining in the prefrontal cortex (infralimbic area), thalamus (midline and reticular nuclei), amygdala, Ammon's horn, dentate gyrus, and entorhinal cortex. These tissue changes correlated with seizure frequency and impairments in sensorimotor gating. Our work indicates that chronic seizures might impact the inhibitory-excitatory balance in the temporal lobe and its interconnected limbic regions, which could increase the likelihood of cognitive deficits and interictal psychiatric disorders.

Indução prévia de LTP na via CA1-córtex pré-frontal medial de ratos bloqueia os prejuízos de plasticidade pré-sináptica induzidos por modelo de psicose pós-ictal in vivo / Prevention of the CA1-mPFC pre-synaptic plasticity impairments in a post-ictal psychosis model 'in vivo'

O objetivo do presente trabalho foi testar se a indução de potenciação de longa duração (LTP) no córtex frontal seria capaz de bloquear os efeitos depressores sobre a plasticidade pré-sináptica da via hipocampo (CA1)-córtex pré-frontal medial (mPFC) induzidos por pós-descarga no hipocampo (AD; atividade epiléptica) ou pela injeção sistêmica de cetamina (KET; modelo farmacológico de psicose). Ratos anestesiados com uretana receberam implantes de eletrodos de estimulação e registro, em CA1 e mPFC, respectivamente. Estímulos elétricos monofásicos pareados foram aplicados em CA1 a cada 20s para eliciar potenciais pós-sinápticos de campo (P1 e P2) no mPFC. Avaliamos a plasticidade de curta duração através da facilitação por pulso pareado (PPF), definida pela razão entre as amplitudes de P2 e P1. Após 90min de registros de linha de base, grupos independentes de animais receberam aplicação de AD, injeção de KET-S(+) (12,5 mg/kg i.p.) ou injeção de veículo (NaCl 0,15M), e foram registrados por mais 120min. Em outro experimento registramos 30min de linha de base e aplicamos estímulos de alta frequência (HFS) para indução de LTP aos 30 e 60min. Trinta minutos depois, os animais receberam KET, AD ou veículo e tiveram seus potenciais corticais registrados por mais 120 min. Nossos resultados mostram que AD gera significativa redução (-50%) da eficiência de transmissão basal na via CA1-mPFC, enquanto KET promove leve aumento (+10%). Ambos os tratamentos também promovem prejuízo significativo da PPF na mesma via (-15%). Além disso, observamos que a indução prévia de LTP atenua as alterações da eficiência basal e bloqueia os prejuízos da PPF na via CA1-mPFC induzidos por KET e AD. Nossos achados reforçam evidências recentes de que moduladores alostéricos positivos de NMDA e AMPA atenuam os prejuízos cognitivos em modelos animais de psicose. Acreditamos, portanto, que a aplicação prévia de HFS na região CA1 do hipocampo pode ser uma ferramenta útil para melhor entendermos como prevenir os prejuízos de plasticidade sináptica no mPFC em modelos de psicose e psicose pós-ictal.

The present work aimed to test whether the induction of cortical long-term potentiation (LTP) was able to prevent the presynaptic plasticity impairment in the hippocampus (CA1)-medial prefrontal cortex (mPFC) pathway induced by hippocampal after-discharge (AD; epileptic activity) or systemic injection of ketamine (KET; pharmacological model of psychosis). Electrodes were stereotaxically positioned into CA1 and mPFC in urethane-anesthetized rats. Monophasic paired-pulses of electrical stimuli were applied to CA1 in order to evoke field post-synaptic potentials (P1 and P2) in the mPFC every 20s. Short-term plasticity was evaluated by measuring paired-pulse facilitation (PPF), defined as the amplitude ratio P2/P1. After 90min of baseline recordings, three independent groups of animals received hippocampal-AD, KET-S(+) (12.5mg/kg, i.p.) or vehicle (NaCl 0.15M) followed by 120min of evoked response monitoring. In an additional experiment, two applications of high-frequency stimuli (HFS) were given at 30 and 60min after baseline. Thirty minutes after the second HFS, the rats received KET, AD or vehicle and their cortical evoked potentials were monitored for further 120min. Our results showed that AD significantly decreased (-50%) whereas KET enhanced (+10%) CA1-mPFC basal synaptic transmission. In addition, AD and KET similarly impaired short-term plasticity in the mPFC (-15%). Interestingly, pre-induction of LTP in the mPFC prevented the PPF disruption induced by KET and AD. Altogether, our findings support recent evidences that positive allosteric modulators of NMDA and AMPA receptors attenuate cognitive impairments in animal models of psychosis. We believe that controlled HFS in CA1 can be a useful tool to better understand how to prevent synaptic plasticity disruptions observed in experimental models of psychosis and pos-ictal psychosis.

Muscarinic acetylcholine neurotransmission enhances the late-phase of long-term potentiation in the hippocampal-prefrontal cortex pathway of rats in vivo: a possible involvement of monoaminergic systems.

The prefrontal cortex is continuously required for working memory processing during wakefulness, but is particularly hypoactivated during sleep and in psychiatric disorders such as schizophrenia. Ammon's horn CA1 hippocampus subfield (CA1) afferents provide a functional modulatory path that is subjected to synaptic plasticity and a prominent monoaminergic influence. However, little is known about the muscarinic cholinergic effects on prefrontal synapses. Here, we investigated the effects of the muscarinic agonist, pilocarpine (PILO), on the induction and maintenance of CA1-medial prefrontal cortex (mPFC) long-term potentiation (LTP) as well as on brain monoamine levels. Field evoked responses were recorded in urethane-anesthetized rats during baseline (50 min) and after LTP (130 min), and compared with controls. LTP was induced 20 min after PILO administration (15 mg/kg, i.p.) or vehicle (NaCl 0.15 M, i.p.). In a separate group of animals, the hippocampus and mPFC were microdissected 20 min after PILO injection and used to quantify monoamine levels. Our results show that PILO potentiates the late-phase of mPFC LTP without affecting either post-tetanic potentiation or early LTP (20 min). This effect was correlated with a significant decrease in relative delta (1-4 Hz) power and an increase in sigma (10-15 Hz) and gamma (25-40 Hz) powers in CA1. Monoamine levels were specifically altered in the mPFC. We observed a decrease in dopamine, 5-HT, 5-hydroxyindolacetic acid and noradrenaline levels, with no changes in 3,4-hydroxyphenylacetic acid levels. Our data, therefore, suggest that muscarinic activation exerts a boosting effect on mPFC synaptic plasticity and possibly on mPFC-dependent memories, associated to monoaminergic changes.