Contextual fear conditioning for predicting immunotherapeutic efficacy

A method for identifying an immunotherapeutic agent effective for improving cognition in a subject suffering from a cognitive disorder, comprising the steps of:

• (i) administering a test immunotherapeutic agent to a model animal of the disorder wherein the model animal exhibits a cognitive deficit;
• (ii) conducting at least one training session in which the model animal is administered a context-dependent stimulus that is paired with an aversive stimulus;
• (iii) conducting at least one testing session in which the model animal is administered a context-dependent stimulus in the absence of the aversive stimulus;
• and
• (iv) comparing a context-dependent fear response of the model animal in step (iii) to an appropriate control,
• whereby an improvement in context-dependent fear response identifies the immunotherapeutic agent as effective for improving cognition in the subject.

A method for identifying an immunotherapeutic agent effective in neutralizing one or more toxic soluble forms of Aβ peptide, comprising the steps of:

• (i) administering a test immunotherapeutic agent to a model animal of an amyloidogenic disorder wherein the model animal exhibits a cognitive deficit;
• (ii) conducting at least one training session in which the model animal is administered a context-dependent stimulus that is paired with an aversive stimulus;
• and
• (iii) conducting at least one testing session in which the model animal is administered a context-dependent stimulus in the absence of the aversive stimulus,
• whereby an improvement in context-dependent memory identifies the immunotherapeutic agent as effective in neutralizing one or more toxic soluble forms of Aβ peptide.

A method of identifying an epitope in an Aβ peptide comprising the steps of:

• (i) administering a fragment of the Aβ peptide to a model animal of an amyloidogenic disorder wherein the model animal exhibits a cognitive deficit;
• (ii) conducting at least one training session in which the model animal is administered a context-dependent stimulus that is paired with an aversive stimulus;
• and
• (iii) conducting at least one testing session in which the model animal is administered a context-dependent stimulus in the absence of the aversive stimulus,
• whereby an improvement in context-dependent memory identifies an epitope in the Aβ peptide.

A method for identifying an immunotherapeutic agent effective for improving cognition in a subject suffering from a cognitive disorder, the method comprising the steps of:

• (i) administering an Aβ peptide to a model animal of an amyloidogenic disorder wherein the model animal exhibits a cognitive deficit;
• (ii) conducting at least one training session in which the model animal is administered a context-dependent stimulus that is paired with an aversive stimulus;
• and
• (iii) conducting at least one testing session in which the model animal is administered a context-dependent stimulus when the in vivo concentration of the test immunotherapeutic agent is more than 50% of the dose administered in step (i),
• whereby an improvement in context-dependent memory identifies the immunotherapeutic agent as effective in improving cognition in the subject.

A method for identifying an immunotherapeutic agent effective for improving cognition in a subject suffering from a cognitive disorder, the method comprising the steps of:

• (i) administering a test immunotherapeutic agent to a model animal of the disorder wherein the model animal exhibits a cognitive deficit;
• (ii) conducting at least one training session in which the model animal is administered a context-dependent stimulus that is paired with an aversive stimulus;
• (iii) conducting at least one testing session in which the model animal is administered a context-dependent stimulus in the absence of the aversive stimulus;
• and
• (iv) comparing a context-dependent fear response of the model animal in step (iii) to a context-dependent fear response of a wild-type animal administered the test immunotherapeutic,
• whereby a nonsignificant difference in status of impairment of the model animal as compared to the wild-type animal identifies the test immunotherapeutic agent as effective in improving cognition in the subject.

A method for identifying an immunotherapeutic agent effective for improving cognition in a subject suffering from a cognitive disorder, the method comprising the steps of:

• (i) administering a test immunotherapeutic agent to a model animal of the disorder wherein the model animal exhibits a cognitive deficit;
• (ii) conducting at least one training session in which the model animal is administered a context-dependent stimulus that is paired with an aversive stimulus;
• (iii) conducting at least one testing session in which the model animal is administered a context-dependent stimulus in the absence of the aversive stimulus;
• and
• (iv) comparing a context-dependent fear response of the model animal in step (iii) to a context-dependent fear response of a model animal that is not administered the test immunotherapeutic agent,
• whereby a significant difference in deficit reversal of the model animal in step (iii) as compared to the model animal that is not administered the test immunotherapeutic agent identifies the test immunotherapeutic agent as effective in improving cognition.

A method for identifying an immunotherapeutic agent effective for improving cognition in a subject suffering from a cognitive disorder, the method comprising the steps of:

• (i) administering a test immunotherapeutic agent to a model animal of the disorder wherein the model animal exhibits a cognitive deficit;
• (ii) conducting at least one training session in which the model animal is administered a context-dependent stimulus that is paired with an aversive stimulus;
• (iii) conducting at least one testing session in which the model animal is administered a context-dependent stimulus in the absence of the aversive stimulus;
• and
• (iv) comparing a context-dependent fear response of the model animal in step (iii) to a context-dependent fear response of a wild-type animal administered the test immunotherapeutic;
• (v) comparing a context-dependent fear response of the model animal in step (iii) to a context-dependent fear response of a model animal that is not administered the test immunotherapeutic agent,
• whereby a nonsignificant difference in status of impairment of the model animal as compared to the wild-type animal and a significant difference in deficit reversal of the model animal in step (iii) as compared to the model animal that is not administered the test immunotherapeutic agent identifies the test immunotherapeutic agent as effective in improving cognition.