Prenatal protein malnutrition decreases neuron numbers in the parahippocampal region but not prefrontal cortex in adult rats

ABSTRACT

Objective: Prenatal protein malnutrition produces anatomical and functional changes in the developing brain that persist despite immediate postnatal nutritional rehabilitation. Brain networks of prenatally malnourished animals show diminished activation of prefrontal areas and an increased activation of hippocampal regions during an attentional task [1]. While a reduction in cell number has been documented in hippocampal subfield CA1, nothing is known about changes in neuron numbers in the prefrontal or parahippocampal cortices.

Methods: In the present study, we used unbiased stereology to investigate the effect of prenatal protein malnutrition on the neuron numbers in the medial prefrontal cortex and the cortices of the parahippocampal region that comprise the larger functional network.

Results: Results show that prenatal protein malnutrition does not cause changes in the neuronal population in the medial prefrontal cortex of adult rats, indicating that the decrease in functional activation during attentional tasks is not due to a reduction in the number of neurons. Results also show that prenatal protein malnutrition is associated with a reduction in neuron numbers in specific parahippocampal subregions: the medial entorhinal cortex and presubiculum.

Discussion: The affected regions along with CA1 comprise a tightly interconnected circuit, suggesting that prenatal malnutrition confers a vulnerability to specific hippocampal circuits. These findings are consistent with the idea that prenatal protein malnutrition produces a reorganization of structural and functional networks, which may underlie observed alterations in attentional processes and capabilities.

KEYWORDS:

• Prenatal protein malnutrition
• stereology
• parahippocampal region
• prefrontal cortex
• medial entorhinal cortex
• malnutrition
• brain development
• neuroanatomy‌

Acknowledgements

Anomymized for review.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This work was supported by National Institutes of Health [grant number HD060896]; National Institutes of Health: [grant number MH078411]; Cole Fund.

Notes on contributors

A. C. Amaral

A. C. Amaral, PhD, received her BS in Nutrition from Centro Universitário Newton Paiva (Brazil) and her PhD in Anatomy and Neurobiology from Boston University, where her research focused on understanding the long-term effects of malnutrition in the brain. After her PhD, she shifted her focus to investigating the mechanisms that lead to neurodegenerative diseases in the aging brain. She is currently a Scientist in Translational Neuropathology at Biogen Inc.

J. P. Lister

J. P. Lister, Ph.D. is an Associate Professor in the Department of Pathology and Laboratory Medicine at the University of California, Los Angeles. He received a B.S. in Biology from Georgetown University and a Ph.D. in Anatomy and Neurobiology from Boston University. His research interests have included the structure and function of medial temporal lobe structures and the development of automated methods for morphological analysis.

J. W. Rueckemann

J. W. Rueckemann, Ph.D. is a comparative neurophysiologist and research assistant professor in the Department of Physiology and Biophysics at the University of Washington. He completed his PhD at Boston University and a postdoctoral fellowship at the University of Washington. His studies hippocampal neurophysiology in rodents and non-human primates to investigate the experiential factors and intrinsic circuit mechanisms that shape the neuronal basis of memory function.

M. W. Wojnarowicz

M. W. Wojnarowicz, PhD, MBA is a Commercial Strategy & Analytics Manager at MilliporeSigma, a business of Merck KGaA, Darmstadt, Germany. He received his BA in biology from Boston University and his PhD in Pathology from Boston University School of Medicine. His thesis research centered on model validation, pathological mechanisms, and diagnostic biomarkers of Chronic Traumatic Encephalopathy. Mark recently earned his MBA with a focus in business analytics from the University of Massachusetts.

J. A. McGaughy

J. A. McGaughy, PhD, is a Professor of Psychology at the University of New Hampshire. She received her BA in psychology from Bradley University and M.A./PhD in psychology from Ohio State University. Her research has focused on the neuromodulatory systems that underlie executive function, the development of these systems from adolescence to adulthood and the impact of early life insults on both the brain and cognition.

D. J. Mokler

D. J. Mokler, PhD, is Professor Emeritus of Biomedical Sciences at the University of New England College of Osteopathic Medicine. He received his BS in psychology and PhD in pharmacology/toxicology and neuroscience from Michigan State University. His research has focused on the organization of the serotonergic, dopaminergic and noradrenergic systems of the limbic system of the brain. He has worked on the functional neuroanatomy of the serotonergic system of the forebrain, the effects of drugs of abuse on the limbic system and the effects of exposure to prenatal protein malnutrition on the function of these systems in the adult rat brain.

J. R. Galler

J. R. Galler, M.D. is a Professor of Psychiatry at Harvard Medical School and Psychiatrist in the Chester M. Pierce MD Division of Global Psychiatry at the Massachusetts General Hospital. She received her undergraduate degree from Sophie Newcomb College and an M.D. From the Albert Einstein College of Medicine. Dr. Galler studies the effects of childhood malnutrition throughout the lifespan and across generations. Her unique, 45+ year study which is based in Barbados examines the impact of early childhood malnutrition on adult survivors and their children and grandchildren.

D. L. Rosene

D. L. Rosene, PhD is Professor of Anatomy & Neurobiology at the Boston University Chobanian and Avedisian School of Medicine. He received his AB in Psychology from Stanford University and his PhD in Psychology and Neurobiology from the University of Rochester. His research investigates the neurobiological bases of learning, memory and executive system function in the brain. A major focus is on how these functions are affected by frank brain damage and by myelin changes that occur in normal aging. A related focus is on recovery of function after circumscribed damage in the monkey cortex and another is how prenatal protein malnutrition affects the brain and cognitive functions in the laboratory rat.

R. J. Rushmore

R. J. Rushmore, Ph.D. is an Associate Professor of Anatomy and Neurobiology at the Boston University Chobanian and Avedisian School of Medicine School of Medicine, and the chief neuroanatomist at the Center for Morphometric Analysis at Massachusetts General Hospital. He received his B.S. in neuroscience from Trinity College, and his Ph.D. in Anatomy and Neurobiology from Boston University. His research interests include alterations of brain structure and function after pre-and perinatal insults, functional recovery and paradoxical effects after brain damage, non-invasive brain stimulation, and morphometric and diffusion MRI-based brain analysis.