Cognitive Assessment

InterVivo Solutions offers a capability for assessment of NCEs in rodent and canine tests of cognition, providing an opportunity to identify efficacy for therapeutic indications associated with a cognitive disorder, and to support safety assessment of novel NCEs. Multiple tests are selected to offer a broad analysis of drug effects against distinct cognitive domains. Various means to challenge cognitive function are available, from natural (aging, task manipulation) to pharmacological. Some of these tests have direct human equivalents offering translational approaches to studying NCEs.

The Morris Water Maze is a test of spatial learning and memory. Various test designs are available although a typical design may involve an initial cued learning phase (visible platform of variable location) followed by a hidden platform test phase (hidden platform of fixed location). Probe tests (i.e., platform removed) conducted at various stages of the hidden platform test phase serve to examine accuracy of spatial learning and retention of this information. The test is readily adaptable to both the rat and mouse, and virtual technology has enabled equivalent tests to be conducted in humans.

Validation Data: Age-dependent impairment in learning and memory assessed by the water maze task.
Water Maze figure

This test of recognition memory is based on the tendency of rodents to preferentially explore a novel compared to a familiar object. Test subjects are exposed to a sample stimulus (object), and after a delay of minutes to hours, are presented with the sample object together with a novel object. Memory of the familiar object is gauged by a time difference score spent exploring each object.

Validation Data: Age-dependent impairment in learning and memory assessed by the novel object recognition task.
Novel object recognition bar chart
Aged rats show a decline in novel object recognition at 3h post sample stage, unlike young controls. Both young and aged rats show decline at 24h post sample stage.

The 5-choice serial reaction time task (5-CSRTT) has become a widely used test to measure attentional perfermance in rodents, and having evolved from the continuous performance test in humans, the test has translational value. The basic test design involves training animals to respond to a brief visual stimulus presented unpredictably in one of five locations. One of the strengths of the 5-CSRTT is the ability to manipulate various test conditions to tax animals and provides a means of detecting bidirectional effects on performance within the same experiment.

Validation Data: Effect of nicotine (0.4mg/kg s.c.) against a vigilance decrement in aged rats
Aged rats (~20mos.) were trained to stable performance levels in the 5-CSRTT, and subjected to occasional tests of extended trials (250 trials per session, 0.5s SD, 5s ITI). Acute nicotine pretreatment (0.4mg/kg s.c.) prevented the within-session decline in accuracy and response speed seen in vehicle treated animals. Cumulative data are shown on the histobars. (Adapted from: Grottick and Higgins, 2002).
5-choice serial task figure
Validation Data: Effect of donepezil (0.3-3mg/kg) on recognition memory assessed using the novel object recognition task. Relationship of dose response to cholinomimetic signs.

Donepezil (Aricept®) (0.3-1mg/kg) produced a clear tendency to improve exploration of a novel object relative to a familiar object in a 24h retention test. No such effect was evident at a higher dose of 3mg/kg. In parallel studies, while donepezil doses of 0.3-1mg/kg had minimal effects on locomotor activity and signs reflective of cholinomimetic activity (secretory signs, tremor, hypothermia), the 3mg/kg dose of donepezil produced hypolocomotion and a clear incidence of cholinomimetic signs in 7/8 animals 0-2h post dose, which likely contributed to the decline in novel object recognition test performance.

Operant tests provide an opportunity to challenge rodents in very specific ways, including, but not limited to, tests to examine specific cognitive domains. Furthermore because animals are typically well trained in these tasks, baseline performance can be tightly controlled and performance becomes predictable. Thus, effects of NCEs can be evaluated against a robust baseline. InterVivo has considerable experience in multiple operant procedures including those to examine motivation (e.g. progressive ratio), behavioral flexibility (e.g., reversal learning) and response inhibition (e.g., Differential Low Rates of Reinforcement (DRL), Go-NoGo). Through the use of a flexible system and relevant proven research experience, InterVivo has the capability to conduct multiple schedules tailored to suit client needs.

Validation Data: Effect of dizocilpine (0.03-0.06 mg/kg s.c.) on two tests of response control in rats
Operant platform figures
Separate groups of adult rats were trained to stable performance levels in the DRL24s task and a signaled Go-NoGo successive discrimination task. In the DRL24s task, vehicle treated rats had peak responding around 24s consistent with accurate temporal discrimination. Dizocilpine (0.03mg/kg s.c.) produced a leftward shift in this response curve. In the Go-NoGo task, in vehicle treated animals, >90% responding was made during the S+ (i.e., Go) phase. Dizocilpine (0.03-0.06mg/kg s.c.) increased responding during the S- (i.e. NoGo) phase, such that only ~75% responding was during the S+ phase. Both tests highlight deficiencies in response control of rats following dizocilpine treatment.

InterVivo provides two tests of increasing difficulty that target this cognitive domain; the delayed non-matching to position test (DNMP) and the serial list learning task (SLL). Various test designs are available although a typical design may involve testing acute effects of an NCE on a variable-delay paradigm that allows assessment of rapid memory enhancing or impairing effects, or on long-term prevention on the progressive decline seen with age. The tests are readily adaptable to man and both MCI and Alzheimer's patients show impairment on variations of these tasks compared to normal controls. These tasks are particularly sensitive to drugs targeting the cholinergic system, including the cholinesterase inhibitors.

To examine this cognitive domain, InterVivo uses a variable-object discrimination paradigm that reveals deficits related to both aging and difficulty. Impairment of selective attention occurs early in pathological aging and is impaired in various neuropsychiatric disorders such as schizophrenia. In this task, a dog is trained to respond to one object of two. Once learned, increasing the number of distracters (incorrect objects) impairs performance and increases response latency. This is augmented with aging, which is may reflect impaired inhibitory control and processing speed, respectively, and by increasing task difficulty. This test has been effective in identifying therapeutics that enhance metabolic and mitochondrial function.

Discrimination and reversal learning are tests of simple learning and executive function, respectively, and the latter is severely impaired with age in multiple species and in Alzheimer's patients. Fine analysis of reversal data can indicate whether NCEs affect perseverance (inhibitory control) or general learning, and this test has been effective in optimizing dose selection.

InterVivo encourages and provides tests to assess the effects of NCEs across several cognitive domains. This approach can be useful for dose optimization and to better understand the broader or selective effects of cognitive-modifying NCEs. Additional cognitive tests that have been validated in the dog include, but are not limited to:

  • Allocentric spatial learning and performance - the landmark task;
  • Egocentric learning and reversal - the egocentric task;
  • Complex learning - oddity discrimination learning; and
  • Psychomotor function - paw reaching task.