Schizophrenia is a heterogeneous psychiatric disorder that is poorly treated with current therapies. In this brief review, we provide an update regarding the use of animal models to study ...schizophrenia in an attempt to understand its aetiology and develop novel therapeutic strategies. Tremendous progress has been made developing and validating rodent models that replicate the aetiologies, brain pathologies, and behavioural abnormalities associated with schizophrenia in humans. Here, models are grouped into 3 categories—developmental, drug induced, and genetic—to reflect the heterogeneous risk factors associated with schizophrenia. Each of these models is associated with varied but overlapping pathophysiology, endophenotypes, behavioural abnormalities, and cognitive impairments. Studying schizophrenia using multiple models will permit an understanding of the core features of the disease, thereby facilitating preclinical research aimed at the development and validation of better pharmacotherapies to alter the progression of schizophrenia or alleviate its debilitating symptoms.
Long-term depression in the CNS Collingridge, Graham L; Peineau, Stephane; Howland, John G ...
Nature reviews. Neuroscience,
07/2010, Letnik:
11, Številka:
7
Journal Article
Recenzirano
Long-term depression (LTD) in the CNS has been the subject of intense investigation as a process that may be involved in learning and memory and in various pathological conditions. Several ...mechanistically distinct forms of this type of synaptic plasticity have been identified and their molecular mechanisms are starting to be unravelled. Most studies have focused on forms of LTD that are triggered by synaptic activation of either NMDARs (N-methyl-D-aspartate receptors) or metabotropic glutamate receptors (mGluRs). Converging evidence supports a crucial role of LTD in some types of learning and memory and in situations in which cognitive demands require a flexible response. In addition, LTD may underlie the cognitive effects of acute stress, the addictive potential of some drugs of abuse and the elimination of synapses in neurodegenerative diseases.
Although NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) of glutamatergic transmission are candidate mechanisms for long-term spatial memory, the precise ...contributions of LTP and LTD remain poorly understood. Here, we report that LTP and LTD in the hippocampal CA1 region of freely moving adult rats were prevented by NMDAR 2A (GluN2A) and 2B subunit (GluN2B) preferential antagonists, respectively. These results strongly suggest that NMDAR subtype preferential antagonists are appropriate tools to probe the roles of LTP and LTD in spatial memory. Using a Morris water maze task, the LTP-blocking GluN2A antagonist had no significant effect on any aspect of performance, whereas the LTD-blocking GluN2B antagonist impaired spatial memory consolidation. Moreover, similar spatial memory deficits were induced by inhibiting the expression of LTD with intrahippocampal infusion of a short peptide that specifically interferes with AMPA receptor endocytosis. Taken together, our findings support a functional requirement of hippocampal CA1 LTD in the consolidation of long-term spatial memory.
Accurate discrimination of environmental cues predicting reward, fear, or safety is important for survival. The prelimbic and infralimbic cortices are implicated in regulating reward-seeking and fear ...behaviors; however, no studies have examined their roles in discriminating among reward, fear, and safety cues. Using a discriminative conditioning task that includes presentations of a reward cue (paired with a reward pellet), fear cue (paired with footshock), and a compound fear+safety cue (no footshock) within the same sessions allowed us to assess the flexibility and precision of fear and reward-seeking behaviors to these cues. We found that fear behavior was appropriately limited to the fear cue in untreated rats, but during infralimbic cortical inactivation, similar levels of fear were seen to the fear and compound fear+safety cues. Reward-seeking behavior was also appropriately limited to the reward cue in untreated rats. Inactivating the prelimbic cortex altered discriminative reward seeking as rats with prelimbic inactivation did not increase their reward seeking behavior during the reward cue to the same degree as saline controls. Our results imply dissociable roles of the two cortical regions: the prelimbic cortex in precise discriminative reward seeking and the infralimbic cortex in discriminating between fear and safety cues. These data suggest that alterations in the balance of activity between areas homologous to the prelimbic and infralimbic cortices may be involved in the processes that go awry in anxiety and addiction disorders.
Emerging evidence implicates rodent medial prefrontal cortex (mPFC) in tasks requiring adaptation of behavior to changing information from external and internal sources. However, the computations ...within mPFC and subsequent outputs that determine behavior are incompletely understood. We review the involvement of mPFC subregions, and their projections to the striatum and amygdala in two broad types of tasks in rodents: 1) appetitive and aversive Pavlovian and operant conditioning tasks that engage mPFC-striatum and mPFC-amygdala circuits, and 2) foraging-based tasks that require decision making to optimize reward. We find support for region-specific function of the mPFC, with dorsal mPFC and its projections to the dorsomedial striatum supporting action control with higher cognitive demands, and ventral mPFC engagement in translating affective signals into behavior via discrete projections to the ventral striatum and amygdala. However, we also propose that defined mPFC subdivisions operate as a functional continuum rather than segregated functional units, with crosstalk that allows distinct subregion-specific inputs (e.g., internal, affective) to influence adaptive behavior supported by other subregions.
•Rodent mPFC helps orchestrate responses under changing/conflicting cue-outcome contingencies and affective valence.•Rodent mPFC performs dynamic, recurrent computations to implement effective strategies during foraging and decision-making.•Functional connectivity between subregions of medial prefrontal cortex and striatum is emphasized.•Priorities for future research are identified.
Synaptic plasticity has often been argued to play an important role in learning and memory. The discovery of long-term potentiation (LTP) and long-term depression (LTD), the two most widely cited ...cellular models of synaptic plasticity, significantly spurred research in this field. Although correlative evidence suggesting a role for synaptic changes such as those seen in LTP and LTD in learning and memory has been gained in a number of studies, definitive demonstrations of a specific role for either LTP or LTD in learning and memory are lacking. In this review, we discuss a number of recent advancements in the understanding of the mechanisms that mediate LTP and LTD in the rodent hippocampus and focus on the use of subunit-specific N-methyl-d-aspartate receptor antagonists and interference peptides as potential tools to study the role of synaptic plasticity in learning and memory. By using the modulation of synaptic plasticity and hippocampal-dependent learning and memory by acute stress as an example, we review a large body of convincing evidence indicating that alterations in synaptic plasticity underlie the changes in learning and memory produced by acute stress.
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan ...dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics. After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics. Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.
Schizophrenia is a complex neuropsychiatric disorder with significant morbidity. Treatment options that address the spectrum of symptoms are limited, highlighting the need for innovative therapeutic ...approaches. Gamma Entrainment Using Sensory Stimulation (GENUS) is an emerging treatment for neuropsychiatric disorders that uses sensory stimulation to entrain impaired oscillatory network activity and restore brain function. Aberrant oscillatory activity often underlies the symptoms experienced by patients with schizophrenia. We propose that GENUS has therapeutic potential for schizophrenia. This paper reviews the current status of schizophrenia treatment and explores the use of sensory stimulation as an adjunctive treatment, specifically through gamma entrainment. Impaired gamma frequency entrainment is observed in patients, particularly in response to auditory and visual stimuli. Thus, sensory stimulation, such as music listening, may have therapeutic potential for individuals with schizophrenia. GENUS holds novel therapeutic potential to improve the lives of individuals with schizophrenia, but further research is required to determine the efficacy of GENUS, optimize its delivery and therapeutic window, and develop strategies for its implementation in specific patient populations.
•GENUS is a novel non-pharmacological therapeutic intervention.•This review examines if GENUS can be applied to schizophrenia.•Specific future research directions in clinical and preclinical models are proposed.
Synaptic plasticity at hippocampal excitatory synapses has been proposed as the cellular mechanism underlying spatial learning and memory. However, most previous studies have focused on the role of ...long-term potentiation (LTP) in learning and memory, and much less is known about the role of long-term depression (LTD). Here, we report that hippocampal-dependent spatial learning in the Morris water maze facilitated hippocampal CA1 LTD induction in vivo. The LTD can be blocked by systemic application of the selective GluN2B antagonist Ro25-6981 (6 mg/kg, i.p.) or a synthetic peptide Tat-GluA23Y (3 μmol/kg, i.p.) that interferes with the endocytosis of AMPA receptors. In addition, systemic or intrahippocampal administration of these two mechanistically and structurally distinct inhibitors impaired spatial reversal learning of a novel target location, when the hidden platform was moved to the quadrant opposite the initial target location. Notably, acute elevated-platform stress, which facilitates hippocampal LTD induction, enhanced both acquisition and retrieval of spatial reversal memory. The present study demonstrates that reversal learning is impaired by blocking hippocampal LTD, and enhanced by facilitating hippocampal LTD, suggesting that hippocampal LTD may be necessary and sufficient to mediate new information processing.
This article is part of a Special Issue entitled ‘Cognitive Enhancers’.
► LTD facilitated by spatial learning depends on GluN2B activation and AMPAR endocytosis. ► Hippocampal LTD may be required for spatial reversal learning. ► Hippocampal LTD may be sufficient to mediate spatial reversal learning.
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