Scott H. Deibel

The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body.

This review consolidates research employing human correlational and experimental work across brain and body with experimental animal models to provide a more complete representation of how circadian rhythms influence almost all aspects of life. In doing so, we will cover the morphological and biochemical pathways responsible for rhythm generation as well as interactions between these systems and others (e.g., stress, feeding, reproduction). The effects of circadian disruption on the health of humans, including time of day effects, cognitive sequelae, dementia, Alzheimers disease, diet, obesity, food preferences, mood disorders, and cancer will also be discussed. Subsequently, experimental support for these largely correlational human studies conducted in non-human animal models will be described.

The effects of chronic photoperiod shifting on the physiology of female Long-Evans rats

As the prevalence of shift work is increasing, it is important to elucidate the impact that shift work has on health. Because of the alternating work schedules present in rotating shift work and working at night, shift workers are in a chronic state of circadian disruption. Animal models of circadian disruption are useful because they offer more experimental control than the largely correlational human shift work studies. The effects of chronic circadian disruption on food preference, glucose tolerance, corticosterone secretion, and performance in a stress-inducing task were investigated in female Long-Evans rats. A 64-day photoperiod shifting paradigm was used to induce circadian disruption. Surprisingly, neither the photoperiod shifted animals, nor the control animals demonstrated a preference for either an unhealthy or healthy diet. Nor was there a difference between the groups in weight gained during photoperiod shifting. However, the photoperiod shifted rats gained significantly more weight than control animals, without eating more food during discriminative fear conditioning to context (DFCTC). Surprisingly, chronic photoperiod shifting appeared to facilitate retention in the DFCTC task. The photoperiod shifted animals also had increased serum glucose values during fasting and after a glucose challenge test. The photoperiod shifted animals only had elevated corticosterone during the final two phases of photoperiod shifting. This study demonstrates that chronic photoperiod shifting elicits weight gain when exposed to a stressful event and impairs glucose tolerance in the same individual.

Barriers to developing a valid rodent model of Alzheimer's disease: from behavioral analysis to etiological mechanisms

Sporadic Alzheimers disease (AD) is the most prevalent form of age-related dementia. As such, great effort has been put forth to investigate the etiology, progression, and underlying mechanisms of the disease. Countless studies have been conducted, however, the details of this disease remain largely unknown. Rodent models provide opportunities to investigate certain aspects of AD that cannot be studied in humans. These animal models vary from study to study and have provided some insight, but no real advancements in the prevention or treatment of the disease. In this Hypothesis and Theory paper, we discuss what we perceive as barriers to impactful discovery in rodent AD research and we offer potential solutions for moving forward. Although no single model of AD is capable of providing the solution to the growing epidemic of the disease, we encourage a comprehensive approach that acknowledges the complex etiology of AD with the goal of enhancing the bidirectional translatability from bench to bedside and vice versa.

Subtle learning and memory impairment in an idiopathic rat model of Alzheimer's disease utilizing cholinergic depletions and β-amyloid.

Alzheimers disease (AD) is a disease of complex etiology, involving multiple risk factors. When these risk factors are presented concomitantly, cognition and brain pathology are more severely compromised than if those risk factors were presented in isolation. Reduced cholinergic tone and elevated amyloid-beta (Aβ) load are pathological hallmarks of AD. The present study sought to investigate brain pathology and alterations in learning and memory when these two factors were presented together in rats. Rats received either sham surgeries, cholinergic depletions of the medial septum, intracerebroventricular Aβ25-35 injections, or both cholinergic depletion and Aβ25-35 injections (Aβ+ACh group). The Aβ+ACh rats were unimpaired in a striatal dependent visual discrimination task, but had impaired acquisition in the standard version of the Morris water task. However, these rats displayed normal Morris water task retention and no impairment in acquisition of a novel platform location during a single massed training session. Aβ+ACh rats did not have exacerbated brain pathology as indicated by activated astroglia, activated microglia, or accumulation of Aβ. These data suggest that cholinergic depletions and Aβ injections elicit subtle cognitive deficits when behavioural testing is conducted shortly after the presentation of these factors. These factors might have altered hippocampal synaptic plasticity and thus resemble early AD pathology.

Boosting weakened synapses to treat Alzheimer’s disease

SummaryThis paper highlights a recent report by Roy and colleagues showing that boosting plasticity in synapses activated during initial memory encoding ameliorates memory impairments found in the early stages of the familial version of Alzheimer’s disease. Our goal was to describe the main features of the report and evaluate the approach and implications of the work.

Cognitive and Stimulus–Response Habit Functions of the Neo-(Dorsal) Striatum

In earlier work, we proposed a theoretical model of dorsal striatal function in which the dorsolateral striatum (DLS) contributes to simple stimulus–response habit formation through reinforcement-based, incremental strengthening of simple S–R bonds via sensorimotor neocortical afferents, whereas the dorsomedial striatum (DMS) contributes to flexible behavior through the cognitive control of responding via inputs from prefrontal and limbic circuits engaged in relational and spatial information processing (Devan et al. 2011). In this chapter, we expand on the original evidence supporting the main hypotheses by further reviewing the neuroanatomical evidence, with particular attention focused on the tripartite model of parallel motor, associate, and limbic loops of the basal ganglia and the open-interconnected circuits allowing for interactions between striatal subregions. In particular, we discuss the idea that blockade of the striosome/patch compartment of the striatum may weaken the integration of higher-order habits based on associative and limbic cortical interactions with the motor-related matrix region. Many recent discoveries support interactive functions of striatal subregions at multiple levels of organization. These interactions modulate different associative learning and performance mechanisms of simple habits and higher-order [(S-S) → R] cognitive–habit integration and behavioral flexibility of associative/limbic interactions with response output and cognitive control function. Neurobehavioral findings show that the striosome/patch compartment within the DMS may normally contribute to the expression of higher-order habit formation that allows cognitive place information acquired through hippocampal/limbic-striatal interaction to access matrix-related reinforcement/response processing under circumstances that promote a cooperative interaction between memory systems. In the second part of the chapter, we review electrophysiological techniques in freely behaving animals. Finally, we present a discussion of Bayesian approaches to the understanding of goal-directed behavior. The role of the dorsal striatum in instrumental learning is particularly amenable to computational models because there are two disparate learning strategies that are posited to be subserved by different neural circuits. Model-free or habit learning has been thought to be primarily mediated by the DLS, whereas model-based or goal directed learning has been thought to rely on the DMS. We review seminal model-free and model-based computations with the goal of integrating them with rodent and human data. We also discuss data suggesting how habit- and goal-directed controllers might interact and finish by highlighting instances that challenge the classic dogma for perceived DLS and DMS function.

The effects of pool shape manipulations on rat spatial memory acquired in the Morris water maze

The Morris water maze is a popular task for examining spatial navigation and memory in rats. Historically, emphasis has been put on extramaze cues as the primary environmental feature guiding navigation and spatial memory formation. However, other features of the environment may also be involved. In this experiment, we trained rats on the spatial version of the Morris water maze over four days. A probe test was given 24 h after training, in which the shape of the pool either remained the same as during training or was changed to a different shape. Mass training of a new platform position in one training session was performed in a pool of one of these two shapes, with a second probe test being done 24 h afterward. The results showed that spatial training produces a spatial preference for the trained location in the probe test when the pool shape remains the same. However, changing the shape of the pool eliminates this preference. All groups learned the new platform position during mass training and also expressed a spatial preference for the mass-trained quadrant when tested 24 h later. The results from these experiments implicate the use of pool shape in guiding spatial navigation in the water maze and as a critical environmental feature represented in spatial memory.

Looking beyond the standard version of the Morris water task in the assessment of mouse models of cognitive deficits

Most studies investigating hippocampal‐dependent learning and memory in mouse models of disease use the standard version of the Morris water task (MWT), in which a place is learned over several days. While useful in determining if there are learning and memory deficits, often it is not clear if memory acquisition, consolidation, or retrieval is affected. For rats, we developed a variant of the task in which we added a single‐massed training session to a new location after the standard distributed version of the MWT. Using this version of the task, competition between these two spatial representations can then be assessed in a probe trial. We have found in rat models of Alzheimers disease that this paradigm can detect subtle impairments that are often missed in the standard version of the MWT. To the best of our knowledge, MWT paradigm with a single‐massed training session have never been used for mice. We sought to validate this paradigm for the use of assessing mouse models of disease. In the first two experiments, control mice did not have a preference for the new platform location, but instead with extensive training in the massed session displayed a preference for both the old and new locations. In the third experiment, a novel mouse model of Alzheimers disease was impaired in the standard version of the MWT, but not in the massed training phase of this paradigm. Importantly, these data demonstrate that our paradigm is more informative in characterizing spatial learning and memory in mouse models of disease.

The Possible Role of Epigenetics in the Memory Impairment Elicited by Circadian Rhythm Disruption

Memories are the glue of one’s existence; unfortunately sometimes memories are more transitory then we would like. Aging and various disease states can induce memory impairments, but for the most part the mechanisms for these memory impairments are largely unknown. Circadian rhythms increase an organism’s biological fitness by synchronizing its physiology and behaviour to their environment. Sometimes circadian rhythms become desynchronized from the environment and this circadian misalignment elicits memory impairments in both humans and rodents. Circadian rhythm dysfunction and memory impairments are hallmarks of both aging and chronic shiftwork, therefore it is pertinent to untangle the nature of the relationship between these processes. Epigenetics allow one’s environment to influence gene expression without changing the genome itself. The plasticity of both memory and circadian rhythms are mediated in part by epigenetic modifications. While epigenetics is necessary for both circadian rhythm generation and memory, very little is known about how circadian rhythm disruption affects the epigenome. Epigenetics will be discussed as a mediator between circadian rhythms and memory in conditions where circadian rhythms are in or out of synch with the environment.