Neonatal lesions of the hippocampus in the rhesus macaque: Testing the validity of the early hippocampal lesion model of schizophrenia in a non-human primate. Open Access

Heuer, Eric David (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/cz30ps943?locale=en
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Abstract

Abstract
Neonatal lesions of the hippocampus in the rhesus macaque:
Testing the validity of the early hippocampal lesion model of schizophrenia
in a non-human primate.
By Eric David Heuer
Schizophrenia is a neurodevelopmental disorder of unknown etiology that has a varied
developmental progression. Research in schizophrenia has found the primary sites of disease
pathology to be the dorsolateral prefrontal cortex (dlPFC) and hippocampus, which are associated
with impairments in working memory and sensory-motor gating. From the knowledge gained
from schizophrenia research, investigators have developed a rodent model in which neonatal
damage to the ventral hippocampus recapitulates a host of neuropathological, behavioral and
cognitive symptoms of the disease state, including impairment in working memory and sensory-
motor gating. Although this rodent model has provided an important tool to better understand the
origins of the disease, interpretation of the cognitive and sensory filtering processes is
problematic because the primary site of pathology in schizophrenia, i.e. the dlPFC, does not truly
exist in the rodent. Thus, to properly address the cognitive problems in schizophrenia and their
neural origin, the use of an animal model with a well-developed prefrontal cortex is required.
Toward this end, the aim of the current studies was to select a battery of neuropsychological,
neuroimaging and sensory-motor assays to measure the effects of neonatal neurotoxic lesions of
the hippocampus in adult monkeys, which have prefrontal regions homologous to those found in
humans. Using monkeys that had received neonatal hippocampal lesions in the first 2 weeks of
life (Neo-H) and sham-operated controls, four experiments were designed. The first two
experiments used cognitive tasks specifically designed to assess monitoring working memory
processes mediated by the dorsolateral prefrontal cortex (i.e. object self-order task and serial
order task) and maintenance working memory processes mediated by the ventrolateral prefrontal
cortex (session-unique delayed non-matching to sample). As compared to controls, monkeys
with Neo-H lesions were impaired on the two former tasks but not on the later, indicating a
selective dlPFC dependent working memory deficit that mirrors that described in schizophrenia.
The results suggest a putative role for the hippocampus in the development of the prefrontal
cortex. To investigate this further, the third experiment directly examined the integrity of
prefrontal cortex regions (dlPFC and vlPFC) in monkeys with Neo-H and their sham-operated
controls using magnetic resonance spectroscopy (MRS). N-acetyl-aspartate (NAA) is an amino
acid, produced exclusively in neurons and consistently associated with cellular integrity and
activity, which can be measured by MRS. The results showed no alterations in the NAA levels
within the dlPFC indicating no evidence of ultra-structural or morphological changes associated
with the Neo-H lesion. By contrast, increased NAA levels were found in the vlPFC, suggesting
that this PFC region may have compensated for a dysfunctional dlPFC by increasing its' activity
levels and subsequently NAA levels. However, given that the vlPFC cannot fully substitute for
all dlPFC functions, monitoring working memory processes mediated by the dlPFC were
disrupted. Lastly, we sought to examine sensory-motor gating following the Neo-H lesion using
the pre-pulse inhibition paradigm (PPI). PPI is known to be sensitive to the disruption of the
ventral striatal circuitry, the same theoretical circuitry whereby early hippocampal lesions are
thought to impact working memory. The results showed no alterations in the baseline startle
response but impairment in inhibition at long pre-pulse intervals. As a whole, these results
suggest that the neonatal lesion model of schizophrenia is tenable in the primate but that the
nature of observed changes may be different than in rodents. Future studies in the primate should
be directed at examining the neural basis for the observed behavioral changes associated with a
Neo-H lesion in a monkey and how it applies to humans.

Table of Contents

Chapter 1. Introduction and Background…………………………………. 1
Overview……………………………………………………………... 1
Schizophrenia Background…………………………………………... 2
Schizophrenia Research…………………...…………………………. 5
Behavioral and Cognitive deficits in Schizophrenia…………………. 9
Schizophrenia Animals Models-Rodent……………………………… 12
Limitations of the Rodent Model…………………………………...… 18
Rhesus Monkey as a Model of Human Cognition……………………. 21
Working Memory………………………………………………….….. 21
Development………………………………………………………...... 35
Conclusion…………………………………………………………..... 40
Hypothesis and Aims………………………………………………….. 41


Chapter 2. Monitoring, but not maintenance, working memory processes are
impaired following selective neonatal lesions of the hippocampus
in the rhesus macaque……..………………………………….. 44

Introduction…………………………………………………………… 44
Methods………………………………………………………………... 47
Subjects……………………………………………………..….. 47
Neuroimaging and Surgical Procedures…………………….… 48
Lesion Assessment……………………………………………… 50
Behavioral Procedures……………………………………...….. 52

Statistical Analysis……………………………………..……… 55
Results………………….…..…………………………………………. 56
Assessment of Lesion Extent………………………………….... 56
SU-DNMS………………………………………………………. 59
Obj-SO………………………………………………………..… 60
Discussion…………………...….……………………………………... 62


Chapter 3. Dorsolateral prefrontal working memory processes are impaired
after selective neonatal lesions of the hippocampus in the adult rhesus
macaque…………………………………………..…………………... 69

Introduction……………………………………..…………………… 69
Methods………………………………………..……………………... 71
Subjects………………………………………………………..... 71
Magnetic Resonance Imaging and Surgical Procedures……….. 73
Lesion Assessment……………………………………………..... 75
Behavioral Procedures……………………………………..…… 77
Results………………………………..……………………………..... 81
Lesion Extent………………………………………………….… 81
3-SOMT…………………………………………………………. 84
4-SOMT………………………………………………………….. 85
4-SOMT Probe Trials……………………………………………. 86
Discussion………………………………………………………... 88

Chapter 4: Magnetic resonance spectroscopy and its relation to working
memory in adult monkeys with neonatal lesions of the hippocampus
………………………………………………………………… 91

Introduction…………..………………………………………….. 91
Methods…………………………………………………………... 94
Subjects……………………………………………………. 94
Magnetic Resonance Imaging and Surgical Procedures…... 95
Lesion Estimation…………………………………………... 97
Magnetic Resonance Spectroscopy (MRS)…..…………....… 99
Statistical Analysis…………………………………………. 101
Results…………………….…………………………………..…. 103
NAA in the dorsolateral prefrontal cortex……….…………. 103
NAA in the ventrolateral prefrontal cortex…………………. 106
NAA in the primary somatosensory cortex………………….. 108
Discussion……………….…………………………………….… 110


Chapter 5: Pre-pulse inhibition deficits in adult monkeys with lesions of
hippocampus and orbital frontal cortex but not the amygdala
…………………………………………………………..….. 115

Introduction…………………….…………………………….... 115
Methods……………………………………………………….... 117
Subjects…………………………………………………….. 117
Neuroimaging and Surgical Procedures………………….... 119
Lesion Assessment…………………………………………... 122

Behavioral Procedures……………………………………... 123
Results………………………………………………………..... 126
Lesion Extent………………………………………………... 126
Startle and PPI…………………....…………………………. 132
Discussion…………………………………………………….... 139


Chapter 6: Overall Discussion, Conclusions and Future Directions… 143
Summary…………………………………………………….… 143
Prefrontal cortical function and working memory……….… 146
Hippocampal effects on working memory…………………… 147
NAA, an interpretation……………………………………….. 148
Implications…………………………………………………… 150
Limitations…………………………………………………….. 151
Future Directions…………………………………………….... 152
References…………………………………………………………….... 155

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