Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability

Background Cellular prion protein (PrPC) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrPC in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrPC is expressed in a number of tissues, including at high levels in the nervous system, especially in neurons and glial cells, and while previous studies have established a neuroprotective role, conflicting evidence for a synaptic function has revealed both reduced and enhanced long-term potentiation, and variable observations on memory, learning, and behavior. Such evidence has been confounded by the absence of an appropriate knock-out mouse model to dissect the biological relevance of PrPC, with some functions recently shown to be misattributed to PrPC due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrPC in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp0/0 mouse model (PrnpZH3/ZH3). Results We performed behavioral and operant conditioning tests to evaluate memory and learning capabilities, with results showing decreased motility, impaired operant conditioning learning, and anxiety-related behavior in PrnpZH3/ZH3 animals. We also carried in vivo electrophysiological recordings on CA3-CA1 synapses in living behaving mice and monitored spontaneous neuronal firing and network formation in primary neuronal cultures of PrnpZH3/ZH3 vs wildtype mice. PrPC absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the PrnpZH3/ZH3 hippocampus. In addition, we observed a delay in neuronal maturation and network formation in PrnpZH3/ZH3 cultures. Conclusion Our results demonstrate that PrPC promotes neuronal network formation and connectivity. PrPC mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.

Conditioning and Associative Learning

Associative learning is the process whereby humans and other animals learn the predictive relationship between cues in their environment. This process underlies simple forms of learning from rewards, such as classical and operant conditioning. In this chapter, we introduce the basics of associative learning and discuss the role that memory processes play in the establishment and maintenance of this learning. We then discuss the role that associative learning plays in human memory, including through paired associate learning, the enhancement of memory by reward, and the formation of episodic memories. Finally, we illustrate how the memory process influences choice in decision-making, where associative learning allows people to learn the values of different options. We conclude with some suggestions about how models of associative learning, memory, and choice can be integrated into a single theoretical framework.

Specific plasticity loci and their synergism mediate operant conditioning

Despite numerous studies examining the mechanisms of operant conditioning (OC), the diversity of plasticity loci and their synergism have not been examined sufficiently. In the well-characterized feeding neural circuit of Aplysia, appetitive OC increases neuronal excitability and electrical coupling among several neurons. Here we found OC decreased the intrinsic excitability of B4 and the strength of its inhibitory connection to a key decision-making neuron, B51. The OC-induced changes were specific without affecting the B4-to-B8 inhibitory connection or excitability of another neuron critical for feeding behavior, B8. A conductance-based circuit model indicated certain sites of plasticity mediated the OC phenotype more effectively and that plasticity loci acted synergistically. This synergy was specific in that only certain combinations of loci synergistically enhanced feeding. Taken together, these results suggest modifications of diverse loci work synergistically to mediate OC.Significance StatementThe diversity and synergism of plasticity loci mediating operant conditioning (OC) is poorly understood. Here we found that OC decreased the intrinsic excitability of a critical neuron mediating Aplysia feeding behavior and specifically reduced the strength of one of its inhibitory connections to a key decision-making neuron. A conductance-based computational model indicated that the known plasticity loci showed a surprising level of synergism to mediate the behavioral changes associated with OC. These results highlight the importance of understanding the diversity, specificity and synergy among different types of plasticity that encode memory. Also, because OC in Aplysia is mediated by dopamine (DA), the present study provides insights into specific and synergistic mechanisms of DA-mediated reinforcement of behaviors.

The reflection of the pandemic experience in contagion (an operant conditioning theory criticism)

This study aims to analyze the reflection on the pandemic circumstances and on the attempts to solve such turmoil as portrayed in the film entitled Contagion. As a sort of literary criticism, this study is qualitative in design. Data collection deals with the use of transcript of the speeches and actions of the characters in particular scenes and certain minutes. For data analysis, this study applies a kind of psychological approach especially Skinner’s Operant Conditioning Theory as means of doing the analytical criticism on the film. The analysis results in the findings such as Contagion illustrates the occurrence of the pandemic as indicated by the presence of the pandemic, its victim and spread. Further, the study also reveals that solution for the pandemic can be performed by the government, society, and individual. This study seems to be significant to inspire and encourage solution for the current pandemic condition.

Return of the Righting Reflex Does Not Portend Recovery of Cognitive Function in Anesthetized Rats

As the number of individuals undergoing general anesthesia rises globally, it becomes increasingly important to understand how consciousness and cognition are restored after anesthesia. In rodents, levels of consciousness are traditionally captured by physiological responses such as the return of righting reflex (RORR). However, tracking the recovery of cognitive function is comparatively difficult. Here we use an operant conditioning task, the 5-choice serial reaction time task (5-CSRTT), to measure sustained attention, working memory, and inhibitory control in male and female rats as they recover from the effects of several different clinical anesthetics. In the 5-CSRTT, rats learn to attend to a five-windowed touchscreen for the presentation of a stimulus. Rats are rewarded with food pellets for selecting the correct window within the time limit. During each session we tracked both the proportion of correct (accuracy) and missed (omissions) responses over time. Cognitive recovery trajectories were assessed after isoflurane (2% for 1 h), sevoflurane (3% for 20 min), propofol (10 mg/kg I.V. bolus), ketamine (50 mg/kg I.V. infusion over 10 min), and dexmedetomidine (20 and 35 μg/kg I.V. infusions over 10 min) for up to 3 h following RORR. Rats were classified as having recovered accuracy performance when four of their last five responses were correct, and as having recovered low omission performance when they missed one or fewer of their last five trials. Following isoflurane, sevoflurane, and propofol anesthesia, the majority (63–88%) of rats recovered both accuracy and low omission performance within an hour of RORR. Following ketamine, accuracy performance recovers within 2 h in most (63%) rats, but low omission performance recovers in only a minority (32%) of rats within 3 h. Finally, following either high or low doses of dexmedetomidine, few rats (25–32%) recover accuracy performance, and even fewer (0–13%) recover low omission performance within 3 h. Regardless of the anesthetic, RORR latency is not correlated with 5-CSRTT performance, which suggests that recovery of neurocognitive function cannot be inferred from changes in levels of consciousness. These results demonstrate how operant conditioning tasks can be used to assess real-time recovery of neurocognitive function following different anesthetic regimens.

Operant conditioning in antlion larvae and its impairment following exposure to elevated temperatures

Although ambush predators were previously considered limited in their cognitive abilities compared to their widely foraging relatives, there is accumulating evidence it does not hold true. Pit-building antlions are already known to associate vibrations in the sand with the arrival of prey. We used a T-maze and successfully trained antlions to turn right or left against their initial turning bias, leading to a suitable substrate for digging traps. We present here the first evidence for operant conditioning and T-maze solving in antlions. Furthermore, we show that exposure of second instar larvae to an elevated temperature led to impaired retention of what was learned in a T-maze when tested after moulting into the third instar, compared to larvae raised under a more benign temperature. We suggest that climate change, involving an increase in mean temperatures as well as rare events (e.g., heatwaves) might negatively affect the retention of operant conditioning in antlions, alongside known, more frequently studied effects, such as changes in body size and distribution.

Animal Training, Environmental Enrichment, and Animal Welfare: A History of Behavior Analysis in Zoos

The modern zoo has been associated with two major behavioral welfare advances: (a) the use of training to increase voluntary husbandry care, and (b) the implementation of environmental enrichment to promote naturalistic behaviors. Both practices have their roots in behavior analysis, or the operant conditioning-centered, reward-based approach to behavioral psychology. Operant conditioning served as the foundation for the development of reinforcement-based training methods commonly used in zoos to make veterinary and husbandry procedures easier and safer for animals and their caregivers. Likewise, operant conditioning, with its focus on arranging environmental antecedents and consequences to change behavior, also provided a framework for successful environmental enrichment practices. In this paper, we outline the key individuals and events that shaped two of the cornerstones of the modern zoo: (1) the emergence of reward-based husbandry training practices, and (2) the engineering of environmental enrichment. In addition, we (3) suggest ways in which behavior analysis can continue to advance zoo welfare by (i) expanding the efficacy of environmental enrichment, (ii) using within-subject methodology, and (iii) improving animal-visitor interactions. Our goal is to provide a historical and contextual reference for future efforts to improve the well-being of zoo animals.

Dynamics of the formation of a differentiation track conditioned reflex to sound stimuli of a certain duration in the gray seal Halichoerus grypus Fabricius, 1791 by the methods of operant conditioning.

In the course of the study, a 15-year-old female gray seal was trained to press a button after displaying an audio signal for 5 seconds and ignore similar audio signals of longer or shorter duration. The conducted research has demonstrated the ability of the experimental seal to reliably differentiate sound signals with a difference in sound duration of 3 seconds. Changes in the reaction time and behavior of the seal during the demonstration of sound stimuli with distinguishable and indistinguishable time ranges are described.