2.2. Derechos Fundamentales:
2.3.5. Filiación Extramatrimonial:
The findings presented in this thesis can be applied across multiple fields of study outside of
the prenatal cocaine model. Infants prenatally exposed to cocaine are considered to be high-risk for
developing many of the behavioral abnormalities commonly seen in other neurodevelopmental
disorders. Many neurodevelopmental/genetic disorders (such as Autism Spectrum Disorder, Williams
syndrome, and Downs syndrome) are associated with altered language development. These
neurodevelopmental disorders are also associated with altered social behavior. Few studies have
explored early communication (i.e. infant vocalizations) in these populations and the impact these
changes might be having on the infant’s environment and hence subsequent development. As
discussed previously infant studies in neurodevelopmental disorders are rare but warranted to
understand how particular phenotypes develop (Jarvinen-Pasley et al., 2008). Altered neonatal
Figure 25.
Schematic of cocaine and environment’s relevant importance to
neurobehavior. Immediately prior and following birth cocaine’s direct effects on the
maternal brain (through neuroendocrinology changes) and fetal brain (through CNS
reactivity) are primarily responsible for initial behavioral profiles in mother and infant.
As the postpartum period progresses environment plays a vital role in long‐term
outcome of both the mother and infant. This behavioral shift to environmental‐driven
behavior we theorize is a critical time in behavioral plasticity when interventions might
hold the most promise.
Birth
(PPD/ PND age)
Weaning
Re
le
va
n
t
Im
port
ance
to
Ne
ur
obeha
vio
r
OT, Estrogen, Progesterone HPA reactivity
Depressed/Excitatory CNS reactivity HPA reactivity
Target Interventions
Cocaine direct impact on maternal brain
Environmental direct impact on maternal brain
Cocaine direct impact on fetal CNS
Environmental direct impact on infant brain
Vulnerable window when
intervention and therapy could
target preventing non‐optimal
developmental outcome
communication could be interfering with the infant’s environment and more directly related to the
atypical development of other behavioral phenotypes, i.e. attention problems commonly observed at
older ages. Longitudinal studies are a necessity to begin to understand how phenotypes develop and
influence others behaviors across a lifespan.
Additionally, many neurodevelopmental disorders are now being linked to alterations in adult
neurogenesis. Adult neurogenesis has been found to be altered in animal models of schizophrenia,
addiction, epilepsy, and mood disorders, and therapies used to treat these disorders normalize
alterations in neurogenesis (Chen et al., 2000;Malberg et al., 2000;Abrous et al., 2005;Pittenger and
Duman, 2008). Most of our current therapies employ treating symptoms of a disorder versus treating
the cause. It is not known if neurogenesis or other neuronal developmental deficits occur as a by-
product of these disorders or as a causative or contributing mechanism, although it is clear that adult
neurogenesis alterations are an important contributor to these complex disorders (for a review see
(Eisch et al., 2008)). The PCE animal model of high-risk infant development employed in the studies
presented here further suggests that altered developmental outcome is a consequence of complex
interactions between infant vulnerability (genetic disorders, prenatal complications, including stress
and drug exposure, etc.) and the postnatal environment (i.e. maternal education, socioeconomic class,
maternal neglect, etc.). Parallel human and animal models, multidisciplinary collaborations,
longitudinal examination of neuronal development, subsequent behavioral manifestation of these
changes, and the role of the environment are all critical for the design and implementation of new
therapeutic strategies and interventions in these populations.
REFERENCES
Abrous DN, Koehl M, Le Moal M (2005) Adult neurogenesis: from precursors to network
and physiology. Physiol Rev 85:523-569.
Adamec RE, Blundell J, Burton P (2003) Phosphorylated cyclic AMP response element
binding protein expression induced in the periaqueductal gray by predator stress: its
relationship to the stress experience, behavior and limbic neural plasticity. Prog
Neuropsychopharmacol Biol Psychiatry 27:1243-1267.
Ahluwalia B, Rajguru S, Kaul L (2010) In Vitro Study Cocaine Decreased Progesterone
Synthesis in the Isolated Cytotrophoblast Cells and in Situ Study PGE2 and PGF2? Levels
Increased N the Amniotic Fluid in Cocaine Users in Humans. pp 32-40.
Akoka S, Descamps P, Genberg C, Franconi F, Arbeille B, Laurini R, Locatelli A, Platt LD,
Arbeille P (1999) Cerebral MRI on fetuses submitted to repeated cocaine administration
during the gestation: an ovine model. Eur J Obstet Gynecol Reprod Biol 85:185-190.
Alessandri SM, Sullivan MW, Bendersky M, Lewis M (1995) Temperament in cocaine-
exposed infants. In: Mothers, babies, and cocaine: the role of toxins in development (Lewis
M, Bendersky M, eds), pp 273-285. Hillsdale,NJ: Lawrence Erlbaum Associates.
Altman J, Bayer SA (1981) Development of the brain stem in the rat. V. Thymidine-
radiographic study of the time of origin of neurons in the midbrain tegmentum. J Comp
Neurol 198:677-716.
Altman J, Bayer SA (1995) Atlas of Prenatal Rat Brain Development. pp 572-575. 2000
Corporate Blvd., N.W., Boca Raton, Florida 33431: CRC Press, Inc.
Antonelli T, Tomasini MC, Tattoli M, Cassano T, Tanganelli S, Finetti S, Mazzoni E,
Trabace L, Steardo L, Cuomo V, Ferraro L (2005) Prenatal exposure to the CB1 receptor
agonist WIN 55,212-2 causes learning disruption associated with impaired cortical NMDA
receptor function and emotional reactivity changes in rat offspring. Cereb Cortex 15:2013-
2020.
Bale TL (2011) Sex differences in prenatal epigenetic programming of stress pathways.
Stress 14:348-356.
Ball SA, Mayes LC, Deteso JA, Schottenfeld RS (1997) Maternal attentiveness of cocaine
abusers during child-based assessments. American Journal on Addictions 6:135-143.
Bandstra ES, Morrow CE, Anthony JC, Churchill SS, Chitwood DC, Steele BW, Ofir AY,
Xue L (2001) Intrauterine growth of full-term infants: impact of prenatal cocaine exposure.
Pediatrics 108:1309-1319.
Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB (2001) Classification
system for malformations of cortical development: update 2001. Neurology 57:2168-2178.
Barr RG, Chen S, Hopkins B, Westra T (1996) Crying patterns in preterm infants. Dev Med
Child Neurol 38:345-355.
Barron S, Gilbertson R (2005) Neonatal ethanol exposure but not neonatal cocaine
selectively reduces specific isolation-induced vocalization waveforms in rats. Behav Genet
35:93-102.
Barron S, Segar TM, Yahr JS, Baseheart BJ, Willford JA (2000) The effects of neonatal
ethanol and/or cocaine exposure on isolation-induced ultrasonic vocalizations. Pharmacol
Biochem Behav 67:1-9.
Bayer SA (1980) Development of the hippocampal region in the rat. II. Morphogenesis
during embryonic and early postnatal life. J Comp Neurol 190:115-134.
Bayer SA, Altman J (1991) Neocortical Development. New York: Raven Press.
Bayer SA, Altman J, Russo RJ, Zhang X (1993) Timetables of neurogenesis in the human
brain based on experimentally determined patterns in the rat. Neurotoxicology 14:83-144.
Beeghly M, Frank DA, Rose-Jacobs R, Cabral H, Tronick E (2003) Level of prenatal cocaine
exposure and infant-caregiver attachment behavior. Neurotoxicol Teratol 25:23-38.
Beeghly M, Martin B, Rose-Jacobs R, Cabral H, Heeren T, Augustyn M, Bellinger D, Frank
DA (2006) Prenatal cocaine exposure and children's language functioning at 6 and 9.5 years:
moderating effects of child age, birthweight, and gender. J Pediatr Psychol 31:98-115.
Behnke M, Eyler FD, Garvan CW, Wobie K, Hou W (2002) Cocaine exposure and
developmental outcome from birth to 6 months. Neurotoxicol Teratol 24:283-295.
Bell SM, Ainsworth MD (1972) Infant crying and maternal responsiveness. Child Dev
43:1171-1190.
Bellini C, Massocco D, Serra G (2005) Prenatal cocaine exposure and the expanding
spectrum of brain malformations. pp 263-275.
Bernstein DP, Stein JA, Handelsman L (1998) Predicting personality pathology among adult
patients with substance use disorders: effects of childhood maltreatment. Addict Behav
23:855-868.
Blake BH (2002) Ultrasonic calling in isolated infant prairie voles (microtus orchrogaster)
and montane voles (m. montanus). pp 536-545.
Blass EM, Camp CA (2003) Changing determinants of crying termination in 6- to 12-week-
old human infants. Dev Psychobiol 42:312-316.
Blumberg MS, Alberts JR (1990) Ultrasonic vocalizations by rat pups in the cold: an acoustic
by-product of laryngeal braking? Behav Neurosci 104:808-817.
Blumberg MS, Alberts JR (1991) On the significance of similarities between ultrasonic
vocalizations of infant and adult rats. Neurosci Biobehav Rev 15:383-390.
Blumberg MS, Efimova IV, Alberts JR (1992) Ultrasonic vocalizations by rat pups: the
primary importance of ambient temperature and the thermal significance of contact comfort.
Dev Psychobiol 25:229-250.
Blumberg MS, Sokoloff G (1998) Thermoregulatory competence and behavioral expression
in the young of altricial species--revisited. Dev Psychobiol 33:107-123.
Blumberg MS, Sokoloff G (2001) Do infant rats cry? Psychol Rev 108:83-95.
Borszcz GS (2006) Contribution of the ventromedial hypothalamus to generation of the
affective dimension of pain. Pain 123:155-168.
Boukydis C (1985) Perception of infant crying as an interpersonal event. In: Lester BM,
Boukydis C, eds. pp 187-216.
Boukydis CF, Burgess RL (1982) Adult physiological response to infant cries: effects of
temperament of infant, parental status, and gender. Child Dev 53:1291-1298.
Branchi I, Santucci D, Alleva E (2001) Ultrasonic vocalisation emitted by infant rodents: a
tool for assessment of neurobehavioural development. Behav Brain Res 125:49-56.
Brazelton TB, Koslowski B, Main M (1974) The origins of reciprocity: the early mother-
infant interaction. In: The effect of the infant on its care-giver (Lewis M, Rosenblum LAE,
eds), New York: Wiley.
Bridges R, Zarrow MX, Gandelman R, Denenberg VH (1972) Differences in maternal
responsiveness between lactating and sensitized rats. Dev Psychobiol 5:123-127.
Bridges RS (1984) A quantitative analysis of the roles of dosage, sequence, and duration of
estradiol and progesterone exposure in the regulation of maternal behavior in the rat.
Endocrinology 114:930-940.
Brooner RK, King VL, Kidorf M, Schmidt CW, Jr., Bigelow GE (1997) Psychiatric and
substance use comorbidity among treatment-seeking opioid abusers. Arch Gen Psychiatry
54:71-80.
Brouette-Lahlou I, Vernet-Maury E, Vigouroux M (1992) Role of pups' ultrasonic calls in a
particular maternal behavior in Wistar rat: pups' anogenital licking. Behav Brain Res 50:147-
154.
Brudzynski SM (2005) Principles of rat communication: quantitative parameters of ultrasonic
calls in rats. Behav Genet 35:85-92.
Brudzynski SM, Kehoe P, Callahan M (1999) Sonographic structure of isolation-induced
ultrasonic calls of rat pups. Dev Psychobiol 34:195-204.
Brudzynski SM, Silkstone M, Komadoski M, Scullion K, Duffus S, Burgdorf J, Kroes RA,
Moskal JR, Panksepp J (2011) Effects of intraaccumbens amphetamine on production of 50
kHz vocalizations in three lines of selectively bred Long-Evans rats. Behav Brain Res
217:32-40.
Brunelli SA, Nie R, Whipple C, Winiger V, Hofer MA, Zimmerberg B (2006) The effects of
selective breeding for infant ultrasonic vocalizations on play behavior in juvenile rats.
Physiol Behav 87:527-536.
Brunelli SA, Shair HN, Hofer MA (1994) Hypothermic vocalizations of rat pups (Rattus
norvegicus) elicit and direct maternal search behavior. J Comp Psychol 108:298-303.
Burgdorf J, Knutson B, Panksepp J, Ikemoto S (2001) Nucleus accumbens amphetamine
microinjections unconditionally elicit 50-kHz ultrasonic vocalizations in rats. Behav
Neurosci 115:940-944.
Burgdorf J, Kroes RA, Moskal JR, Pfaus JG, Brudzynski SM, Panksepp J (2008) Ultrasonic
vocalizations of rats (Rattus norvegicus) during mating, play, and aggression: Behavioral
concomitants, relationship to reward, and self-administration of playback. J Comp Psychol
122:357-367.
Burgdorf J, Wood PL, Kroes RA, Moskal JR, Panksepp J (2007) Neurobiology of 50-kHz
ultrasonic vocalizations in rats: electrode mapping, lesion, and pharmacology studies. Behav
Brain Res 182:274-283.
Burns K, Chethik L, Burns WJ, Clark R (1991) Dyadic disturbances in cocaine-abusing
mothers and their infants. J Clin Psychol 47:316-319.
Byun J, Verardo MR, Sumengen B, Lewis GP, Manjunath BS, Fisher SK (2006) Automated
tool for the detection of cell nuclei in digital microscopic images: application to retinal
images. Mol Vis 12:949-960.
Calizo LH, Flanagan-Cato LM (2002) Estrogen-induced dendritic spine elimination on
female rat ventromedial hypothalamic neurons that project to the periaqueductal gray. J
Comp Neurol 447:234-248.
Campbell CG, Seidler FJ, Slotkin TA (1997) Chlorpyrifos interferes with cell development in
rat brain regions. Brain Res Bull 43:179-189.
Carvalho-Netto EF, Gomes KS, Amaral VC, Nunes-de-Souza RL (2009) Role of glutamate
NMDA receptors and nitric oxide located within the periaqueductal gray on defensive
behaviors in mice confronted by predator. Psychopharmacology (Berl) 204:617-625.
Champagne F, Diorio J, Sharma S, Meaney MJ (2001) Naturally occurring variations in
maternal behavior in the rat are associated with differences in estrogen-inducible central
oxytocin receptors. Proc Natl Acad Sci U S A 98:12736-12741.
Champagne FA, Weaver IC, Diorio J, Sharma S, Meaney MJ (2003) Natural variations in
maternal care are associated with estrogen receptor alpha expression and estrogen sensitivity
in the medial preoptic area. Endocrinology 144:4720-4724.
Chan T, Kyere K, Davis BR, Shemyakin A, Kabitzke PA, Shair HN, Barr GA, Wiedenmayer
CP (2011) The role of the medial prefrontal cortex in innate fear regulation in infants,
juveniles, and adolescents. J Neurosci 31:4991-4999.
Chasnoff IJ (1987) Cocaine- and methadone-exposed infants: a comparison. NIDA Res
Monogr 76:278.
Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK (2000) Enhancement of
hippocampal neurogenesis by lithium. J Neurochem 75:1729-1734.
Chen YL, Li AH, Yeh TH, Chou AH, Wang HL (2009) Nocistatin and nociceptin exert
opposite effects on the excitability of central amygdala nucleus-periaqueductal gray
projection neurons. Mol Cell Neurosci 40:76-88.
Choi BH (1989) The effects of methylmercury on the developing brain. Prog Neurobiol
32:447-470.
Clarke C, Clarke K, Muneyyirci J, Azmitia E, Whitaker-Azmitia PM (1996) Prenatal cocaine
delays astroglial maturation: immunodensitometry shows increased markers of immaturity
(vimentin and GAP-43) and decreased proliferation and production of the growth factor S-
100. Brain Res Dev Brain Res 91:268-273.
Claussen AH, Mundy PC, Mallik SA, Willoughby JC (2002) Joint attention and disorganized
attachment status in infants at risk. Dev Psychopathol 14:279-291.
Collins DR (2011) Synthetic versus natural cat odorant effects on rodent behavior and medial
amygdala plasticity. Behav Neurosci 125:124-129.
Copeland DB, Harbaugh BL (2004) Transition of maternal competency of married and single
mothers in early parenthood. J Perinat Educ 13:3-9.
Corwin MJ, Lester BM, Sepkoski C, McLaughlin S, Kayne H, Golub HL (1992) Effects of in
utero cocaine exposure on newborn acoustical cry characteristics. Pediatrics 89:1199-1203.
Cox ET, Zeskind PS, Pimentel ME, Baxley AD, Deburkarte MJ, Elam MC, Johns JM,
Grewen KM (2010) Cocaine exposure alters maternal sensitivity to infant behavior
predicting infant developmental outcome. Society for Neuroscience: Chicago,IL.
Crowe HP, Zeskind PS (1992) Psychophysiological and perceptual responses to infant cries
varying in pitch: comparison of adults with low and high scores on the Child Abuse Potential
Inventory. Child Abuse Negl 16:19-29.
de Menezes RC, Zaretsky DV, Fontes MA, DiMicco JA (2009) Cardiovascular and thermal
responses evoked from the periaqueductal grey require neuronal activity in the
hypothalamus. J Physiol 587:1201-1215.
Delaney-Black V, Covington C, Templin T, Ager J, Martier S, Sokol R (1998) Prenatal
cocaine exposure and child behavior. Pediatrics 102:945-950.
Deviterne D, Desor D, Krafft B (1990) Maternal behavior variations and adaptations, and
pup development within litters of various sizes in Wistar rat. Dev Psychobiol 23:349-360.
Dominguez-Escriba L, Hernandez-Rabaza V, Soriano-Navarro M, Barcia JA, Romero FJ,
Garcia-Verdugo JM, Canales JJ (2006) Chronic cocaine exposure impairs progenitor
proliferation but spares survival and maturation of neural precursors in adult rat dentate
gyrus. Eur J Neurosci 24:586-594.
Donovan WL (1981) Maternal learned helplessness and physiologic response to infant
crying. J Pers Soc Psychol 40:919-926.
Donovan WL, Leavitt LA, Walsh RO (1990) Maternal self-efficacy: illusory control and its
effect on susceptibility to learned helplessness. Child Dev 61:1638-1647.
Donovan WL, Leavitt LA, Walsh RO (1998) Conflict and depression predict maternal
sensitivity to infant cries. pp 505-517.
Dow-Edwards D (2010) Sex differences in the effects of cocaine abuse across the life span.
Physiol Behav 100:208-215.
Dujardin E, Jurgens U (2005) Afferents of vocalization-controlling periaqueductal regions in
the squirrel monkey. Brain Res 1034:114-131.
Dunty WC, Jr., Chen SY, Zucker RM, Dehart DB, Sulik KK (2001) Selective vulnerability
of embryonic cell populations to ethanol-induced apoptosis: implications for alcohol-related
birth defects and neurodevelopmental disorder. Alcohol Clin Exp Res 25:1523-1535.
Eiden RD, Schuetze P, Coles CD (2011) Maternal cocaine use and mother-infant
interactions: Direct and moderated associations. Neurotoxicol Teratol 33:120-128.
Eiden RD, Chavez F, Leonard KE (1999) Parent-infant interactions among families with
alcoholic fathers. Dev Psychopathol 11:745-762.
Eiden RD, McAuliffe S, Kachadourian L, Coles C, Colder C, Schuetze P (2009a) Effects of
prenatal cocaine exposure on infant reactivity and regulation. Neurotoxicol Teratol 31:60-68.
Eiden RD, Veira Y, Granger DA (2009b) Prenatal cocaine exposure and infant cortisol
reactivity. Child Dev 80:528-543.
Eisch AJ, Cameron HA, Encinas JM, Meltzer LA, Ming GL, Overstreet-Wadiche LS (2008)
Adult neurogenesis, mental health, and mental illness: hope or hype? J Neurosci 28:11785-
11791.
Esposito G, Venuti P (2010) Understanding early communication signals in autism: a study
of the perception of infants' cry. J Intellect Disabil Res 54:216-223.
Eyler FD, Behnke M, Conlon M, Woods NS, Wobie K (1998) Birth outcome from a
prospective, matched study of prenatal crack/cocaine use: II. Interactive and dose effects on
neurobehavioral assessment. Pediatrics 101:237-241.
Fabricius K, Wortwein G, Pakkenberg B (2008) The impact of maternal separation on adult
mouse behaviour and on the total neuron number in the mouse hippocampus. Brain Struct
Funct 212:403-416.
Farrell WJ, Alberts JR (2002a) Maternal responsiveness to infant Norway rat (Rattus
norvegicus) ultrasonic vocalizations during the maternal behavior cycle and after steroid and
experiential induction regimens. J Comp Psychol 116:286-296.
Farrell WJ, Alberts JR (2002b) Stimulus control of maternal responsiveness to Norway rat
(Rattus norvegicus) pup ultrasonic vocalizations. J Comp Psychol 116:297-307.
Feldman JF, Brody N, Miller SA (1980) Sex differences in non-elicited neonatal behaviors.
pp 63-73.
Fleming AS, Walsh C (1994) Neuropsychology of maternal behavior in the rat: c-fos
expression during mother-litter interactions. Psychoneuroendocrinology 19:429-443.
Frank DA, Augustyn M, Knight WG, Pell T, Zuckerman B (2001) Growth, development, and
behavior in early childhood following prenatal cocaine exposure: a systematic review. JAMA
285:1613-1625.
Frodi AM, Lamb M.E., LL, Donovan W., NC, Sherry D. (1978) Fathers' and mothers'
responses to the appearance and cries of premature and normal infants. pp 490-498.
Frodi AM, Lamb ME (1980) Child abusers' responses to infant smiles and cries. Child Dev
51:238-241.
Fu Y, Pollandt S, Liu J, Krishnan B, Genzer K, Orozco-Cabal L, Gallagher JP, Shinnick-
Gallagher P (2007) Long-term potentiation (LTP) in the central amygdala (CeA) is enhanced
after prolonged withdrawal from chronic cocaine and requires CRF1 receptors. J
Neurophysiol 97:937-941.
Galanter M, Kleber HD (2008) The american psychiatric publishing textbook of substance
abuse treatment 4th edition. Arlington, VA: American Psychiatry Publishing, Inc.
Gerardin P, Wendland J, Bodeau N, Galin A, Bialobos S, Tordjman S, Mazet P, Darbois Y,
Nizard J, Dommergues M, Cohen D (2011) Depression during pregnancy: is the
developmental impact earlier in boys? A prospective case-control study. J Clin Psychiatry
72:378-387.
Goldman-Fraser J (1997) Cognitive influences on mother-infant interaction: A focus on
substance-dependent women in treatment during pregnancy and postpartum. University of
North Carolina - Chapel Hill.
Golub HL, Corwin MJ (1985) A physioacoustic model of the infant cry. In: Infant Crying:
Theoretical and Research Perspectives
(Lester BM, Boukydis CFZ, eds), pp 59-82. New
York: Plenum.
Gonzalez-Lima F, Frysztak RJ (1991) Functional mapping of the rat brain during
vocalizations: a 2-deoxyglucose study. Neurosci Lett 124:74-78.
Green JA, Jones LE, Gustafson GE (1987) Perception of cries by parents and nonparents:
Relation to cry acoustics. pp 370-382.
Griffith SD, Shiffman S, Heitjan DF (2009) A method comparison study of timeline
followback and ecological momentary assessment of daily cigarette consumption. Nicotine
Tob Res 11:1368-1373.
Grunau RV, Craig KD (1987) Pain expression in neonates: facial action and cry. Pain
28:395-410.
Grunau RV, Johnston CC, Craig KD (1990) Neonatal facial and cry responses to invasive
and non-invasive procedures. Pain 42:295-305.
Guerri C (1998) Neuroanatomical and neurophysiological mechanisms involved in central
nervous system dysfunctions induced by prenatal alcohol exposure. Alcohol Clin Exp Res
22:304-312.
Gustafson GE, Green JA (1989) On the importance of fundamental frequency and other
acoustic features in cry perception and infant development. Child Dev 60:772-780.
Hahn ME, Benno RH, Schanz N, Phadia E (2000) The effects of prenatal cocaine exposure
