Andrea A. Chiba

Orbitofrontal cortex and basolateral amygdala encode expected outcomes during learning

Reciprocal connections between the orbitofrontal cortex and the basolateral nucleus of the amygdala may provide a critical circuit for the learning that underlies goal-directed behavior. We examined neural activity in rat orbitofrontal cortex and basolateral amygdala during instrumental learning in an olfactory discrimination task. Neurons in both regions fired selectively during the anticipation of rewarding or aversive outcomes. This selective activity emerged early in training, before the rats had learned reliably to avoid the aversive outcome. The results support the concept that the basolateral amygdala and orbitofrontal cortex cooperate to encode information that may be used to guide goal-directed behavior.

Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease

Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimers disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimers disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimers disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimers disease.

Neural Encoding in Orbitofrontal Cortex and Basolateral Amygdala during Olfactory Discrimination Learning

Orbitofrontal cortex (OFC) is part of a network of structures involved in adaptive behavior and decision making. Interconnections between OFC and basolateral amygdala (ABL) may be critical for encoding the motivational significance of stimuli used to guide behavior. Indeed, much research indicates that neurons in OFC and ABL fire selectively to cues based on their associative significance. In the current study recordings were made in each region within a behavioral paradigm that allowed comparison of the development of associative encoding over the course of learning. In each recording session, rats were presented with novel odors that were informative about the outcome of making a response and had to learn to withhold a response after sampling an odor that signaled a negative outcome. In some cases, reversal training was performed in the same session as the initial learning. Ninety-six of the 328 neurons recorded in OFC and 60 of the 229 neurons recorded in ABL exhibited selective activity during evaluation of the odor cues after learning had occurred. A substantial proportion of those neurons in ABL developed selective activity very early in training, and many reversed selectivity rapidly after reversal. In contrast, those neurons in OFC rarely exhibited selective activity during odor evaluation before the rats reached the criterion for learning, and far fewer reversed selectivity after reversal. The findings support a model in which ABL encodes the motivational significance of cues and OFC uses this information in the selection and execution of an appropriate behavioral strategy.

Cognitive functions of the basal forebrain.

Studies of the function of the basal forebrain have focused on cholinergic neurons that project to cortical and limbic structures critical for various cognitive abilities. Recent experiments suggest that these neurons serve a modulatory function in cognition, by optimizing cortical information processing and influencing attention.

Lesions of the Basal Forebrain Cholinergic System Impair Task Acquisition and Abolish Cortical Plasticity Associated with Motor Skill Learning

The contribution of the basal forebrain cholinergic system in mediating plasticity of cortical sensorimotor representations was examined in the context of normal learning. The effects of specific basal forebrain cholinergic lesions upon cortical reorganization associated with learning a skilled motor task were investigated, addressing, for the first time, the functional consequences of blocking cortical map plasticity. Results demonstrate that disrupting basal forebrain cholinergic function disrupts cortical map reorganization and impairs motor learning. Cholinergic lesions do not impair associative fear learning or overall sensorimotor function. These results support the hypothesis that the basal forebrain cholinergic system may be specifically implicated in forms of learning requiring plasticity of cortical representations.

Changes in Functional Connectivity in Orbitofrontal Cortex and Basolateral Amygdala during Learning and Reversal Training

Interconnections between orbitofrontal cortex (OFC) and basolateral amygdala (ABL) are critical for encoding and using associative information about the motivational significance of stimuli. Previously, we reported that neurons in OFC and ABL fired selectively to cues during odor discrimination learning and reversal training. Here we conducted an analysis of correlated firing in the cell pairs recorded in the previous study. Correlated firing during the intertrial intervals was compared across task phases during different phases of acquisition and reversal learning. Changes in correlated activity during initial learning and subsequent accurate performance on the discrimination problems closely resembled the changes in odor selectivity in OFC and ABL reported earlier. Increased correlated firing was most pronounced in OFC during accurate go, no-go performance in the postcriterion phase of performance, whereas correlated firing in ABL increased primarily during an earlier phase of learning. In contrast, findings during subsequent reversal training diverged from our earlier report in which odor selectivity diminished in OFC and reversed in ABL. When the reinforcement contingencies of the odors were reversed after the rat had learned the original associations, correlated firing further increased significantly in OFC but remained stable in ABL. This evidence that associative encoding increments with reversal learning in OFC suggests that the original associations, although not expressed as stimulus driven activity, may be maintained within the network as new associations are acquired.

The Basal Forebrain Cholinergic System Is Essential for Cortical Plasticity and Functional Recovery following Brain Injury

A reorganization of cortical representations is postulated as the basis for functional recovery following many types of nervous system injury. Neuronal mechanisms underlying this form of cortical plasticity are poorly understood. The present study investigated the hypothesis that the basal forebrain cholinergic system plays an essential role in enabling the cortical reorganization required for functional recovery following brain injury. The results demonstrate that functional recovery following cortical injury requires basal forebrain cholinergic mechanisms and suggest that the basis for this recovery is the cholinergic-dependent reorganization of motor representations. These findings raise the intriguing possibility that deficits in cholinergic function may limit functional outcomes following nervous system injury.

Hippocampal cell genesis does not correlate with spatial learning ability in aged rats.

Aging in rodents is known to lead to deficits in spatial learning and memory, including decreased performance on the Morris water maze. Recent attention has focused on the possible role of adult hippocampal neurogenesis in regulating spatial learning and memory. Therefore, in this study, we have examined levels of hippocampal cell proliferation in relation to water maze performance in aged and young male Fischer 344 rats. Aged rats (24 months old) were divided into aged‐unimpaired and aged‐impaired groups based on comparison with performance of young animals. Animals received five daily injections of the thymidine‐analog bromodeoxyuridine (BrdU) and were killed 1 week later. Total numbers of BrdU‐labeled cells were quantified in the hippocampal dentate gyrus and hilus and were related to behavioral performance. Whereas aging was associated with a significant reduction in the number of BrdU‐labeled cells, behavioral impairment with aging was not associated with a further reduction in BrdU labeling. In the context of aging, these finding do not support a direct relationship of adult hippocampal neurogenesis with learning and memory capability. J. Comp. Neurol. 459:201–207, 2003.

Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats.

Despite abundant evidence of behavioral and electrophysiological dysfunction of the rodent hippocampal formation with aging, the structural basis of age‐related cognitive decline remains unclear. Recently, unbiased stereological studies of the mammalian hippocampus have found little evidence to support the dogma that cellular loss accompanies hippocampal aging, thereby supporting an alternative hypothesis that aging is marked by widespread conservation of neuronal number. However, to date, the effects of aging have not been reported in another key component of memory systems in the rodent brain, the entorhinal cortex. In the present study, we stereologically estimated total neuronal number and size (cross‐sectional area and cell volume) in the subdivisions and cellular layers of the rat entorhinal cortex, using the optical fractionator and nucleator, respectively. Comparisons were made among Fischer 344 rats that were young, aged‐impaired, and aged‐unimpaired (based on functional analysis in the Morris water maze). No significant differences in cell number or size were observed in any of the entorhinal subdivisions or laminae examined in each group. Thus, aging is associated with widespread conservation of neuronal number, despite varying degrees of cognitive decline, in all memory‐related systems examined to date. These data suggest that mechanisms of age‐related cognitive decline are to be found in parameters other than neuronal number or size in the cortex of the mammalian brain. J. Comp. Neurol. 438:445–456, 2001.

Selective removal of cholinergic neurons in the basal forebrain alters cued target detection

A spatial orienting task was used to assess attention in rats with selective cholinergic lesions of the basal forebrain. The task required each rat to press a lever in response to a visual target that could occur in one of two locations. A target could be preceded by a cue that either accurately predicted the location of the target (valid) or appeared in the location opposite the target (invalid). Target detection was facilitated by valid cues and degraded by invalid cues in control rats. Performance of rats with lesions was equivalent to that of control rats for valid cues, but reflected an increased cost of invalid cueing. These data support a modulatory role for the basal forebrain cholinergic system in visuospatial attention.