API

Relationship: 359

Title

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Neuronal network function, Decreased leads to Impairment, Learning and memory

Upstream event

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Neuronal network function, Decreased

Downstream event

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Impairment, Learning and memory

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens Strong NCBI
rat Rattus norvegicus Strong NCBI
mouse Mus musculus Strong NCBI

Sex Applicability

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Sex Evidence
Mixed Strong

Life Stage Applicability

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Term Evidence
During brain development Strong

How Does This Key Event Relationship Work

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Learning and memory is one of the outcomes of the functional expression of neurons and neural networks from mammalian to invertebrates. Damage or destruction of neurons by chemical compounds during development when they are in the process of synapses formation, integration and formation of neural networks, will derange the organization and function of these networks, thereby setting the stage for subsequent impairment of learning and memory. Exposure to the potential developmental toxicants during neuronal differentiation and synaptogenesis will increase risk of functional neuronal network damage leading to learning and memory impairment.

Impairments in learning and memory are measured using behavioral techniques. It is well accepted that these alterations in behavior are the result of structural or functional changes in neurocircuitry. Functional impairments are often measured using field potentials of critical synaptic circuits in hippocampus and cortex. A number of studies have been performed in rodent models that reveal deficits in both excitatory and inhibitory synaptic transmission in the hippocampus as a result of developmental thyroid insufficiency (Wang et al., 2012; Oerbeck et al., 2003; Wheeler et al., 2011; Wheeler et al., 2015; Willoughby et al., 2014; Davenport and Dorcey, 1972; Tamasy et al., 1986; Akaike, 1991; Axelstad et al., 2008; Gilbert and Sui, 2006; Gilbert et al., 2016; Gilbert, 2011; Gilbert et al., 2016). A well-established functional readout of memory at the synaptic level is known as long-term potentiation (LTP) (i.e., a persistent strengthening of synapses based on recent patterns of activity). Deficiencies in LTP are generally regarded as potential substrates of learning and memory impairments. In rodent models where synaptic function is impaired by TH deficiencies, deficits in hippocampus-mediated memory are also prevalent (Gilbert and Sui, 2006; Gilbert et al., 2016; Gilbert, 2011; Gilbert et al., 2016).

Weight of Evidence

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A number of studies have consistently reported alterations in synaptic transmission resulting from developmental TH disruption, and leading to decreased cognition.

Developmental hypothyroidism reduces the functional integrity in brain regions critical for learning and memory. Neurophysiological indices of synaptic transmission of excitatory and inhibitory circuitry are impaired in the hippocampus of hypothyroid animals. Both hippocampal regions (area CA1 and dentate gyrus) exhibit alterations in excitatory and inhibitory synaptic transmission following reductions in serum TH in the pre and early postnatal period (Vara et al., 2002; Sui and Gilbert, 2003; Sui et al., 2005; Gilbert and Sui, 2006; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). These alterations persist into adulthood despite a recovery to euthyroid conditions in blood. The latter observation indicates that these alterations represent permanent changes in brain function induced from transient hormones insufficiencies induced during critical window of development.  

Because the adult hippocampus is involved in learning and memory, it is a brain region of remarkable plasticity. Use-dependent synaptic plasticity is critical during brain development for synaptogenesis and fine tuning of synaptic connectivity. In the adult brain, similar plasticity mechanisms underlie use-dependency that underlies learning and memory, as exhibited in LTP model of synaptic memory. Hypothyroidism during development reduces the capacity for synaptic plasticity in juvenile and adult offspring (Vara et al., 2002; Sui and Gilbert, 2003; Dong et al., 2005; Sui et al., 2005; Gilbert and Sui, 2006; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). Decrease of synaptic function and plasticity are observed coincident with deficits in learning tasks that require the hippocampus.

- Wang et al., 2012: This study showed that maternal subclinical hypothyroidism impairs spatial learning in the offspring, as well as the efficacy and optimal time of T4 treatment in pregnancy. Female adult Wistar rats were randomly divided into six groups: control, hypothyroid (H), subclinical hypothyroid (SCH) and SCH treated with T4, starting from GD10, GD13 and GD17, respectively, to restore normal TH levels. Results indicate that progenies of SCH and H groups demonstrated significantly longer mean latency in the water maze test (on the 2nd training day, latency was ~83% higher in H group, and ~50% higher in SCH), and a lower amplification percentage of the amplitude (~15% lower in H group, and 12% lower in SCH), and slope of the field excitatory postsynaptic potential (fEPSP) recording (~20% lower in H group, and 17% lower in SCH), compared to control group. T4 treatment at GD10 and GD13 significantly shortened mean latency and increased the amplification percentage of the amplitude and slope of the fEPSPs of the progeny of rats with subclinical hypothyroidism. However, T4 treatment at GD17 showed only minimal effects on spatial learning in the offspring. Altogether these data indicate direct correlation between decrease of neural network function and learning and memory deficits.

- Liu et al., 2010 This study assessed the effects of hypothyroidism in 60 female rats who were divided into three groups: (i) maternal subclinical hypothyroidism (total thyroidectomy with T4 infusion), (ii) maternal hypothyroidism (total thyroidectomy without T4 infusion), and (iii) control (sham operated). The Morris water maze tests revealed that pups from the subclinical hypothyroidism group showed long-term memory deficits, and a trend toward short-term memory deficits.

- Gilbert and Sui, 2006 Administration of 3 or 10 ppm PTU to pregnant and lactating dams via the drinking water from GD6 until PND30 caused a 47% and 65% reduction in serum T4, in the dams of the low and high-dose groups, respectively. Baseline synaptic transmission was impaired in PTU-exposed animals: mean EPSP slope (by ~60% with 10 ppm PTU) and population spike amplitudes (by ~70% with 10 ppm PTU) in the dentate gyrus were reduced in a dose-dependent manner in adult offspring of PTU-treated dams. High-dose animals (10 ppm) demonstrated very little evidence of learning despite 16 consecutive days of training (~5-fold higher mean latency to find the hidden platform, used as an index of learning).

- Gilbert et al., 2016 Exposure to PTU during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. Developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes in neonate hippocampus and was accompanied by deficits in hippocampal-based learning (e.g., mean latency to find a hidden platform, at 2nd trial resulted ~60% higher in rats treated with 10 ppm PTU).

- Gilbert, 2011 Trace fear conditioning deficits to context and to cue reported in animals treated with PTU and who also displayed synaptic transmission and LTP deficits in hippocampus. Baseline synaptic transmission was impaired in PTU-exposed animals (by ~50% in animal treated with 3 ppm PTU). EPSP slope amplitudes in the dentate gyrus were reduced in a dose-dependent manner in adult offspring of PTU-treated dams.

 

BPA, an environmental toxicant known to inhibit NIS-mediated iodide uptake (Wu Y et al., 2016) has been found to cause learning and memory deficits in rodents as described below:

- Jang et al., 2012 In this study, pregnant female C57BL/6 mice (F0) were exposed to BPA (0.1-10 mg/kg) from gestation day 6 to 17, and female offspring (F2) from F1 generation mice were analysed. Exposure of F0 mice to BPA (10 mg/kg) decreased hippocampal neurogenesis (~ 30% decrease of hippocampal BrdU+ cells vs control) in F2 female mice. High-dose BPA (10 mg/kg) caused neurocognitive deficit (i.e., reduced memory retention) as shown by passive avoidance testing (~ 33% decrease vs control) in F2 mice. Furthermore, 10 mg/kg BPA decreased the hippocampal levels of BDNF (~ 35% lower vs control) in F2 mice. These results suggest that BPA exposure (NIS inhibitor) in pregnant mothers could decrease hippocampal neurogenesis (decreased number of neurons) and cognitive function in future generations.

 

In humans, the data linking these two specific KE are much more limited, but certainly clear reductions in IQ, with specific impairments in hippocampus-mediated functions have been observed.

- Wheeler et al., 2015 This study assessed hippocampal functioning in adolescents with congenital hypothyroidism (CH), using functional magnetic resonance imaging (fMRI). 14 adolescents with CH and 14 typically developing controls (TDC) were studied. Hippocampal activation was greater for pairs than items in both groups, but this difference was only significant in TDC. When the groups were directly compared, the right anterior hippocampus was the primary region in which the TDC and CH groups differed for this pair memory effect. Results signify that adolescents with CH show abnormal hippocampal functioning during verbal memory processing in order to compensate for the effects induced by TH deficit in the brain.

- Wheeler et al., 2012 In this study hippocampal neuronal network function was measured based on synaptic performance using fMRI and was altered while subjects engaged in a memory task. Data showed paired word recognition deficits in adolescents with congenital hypothyroidism (N = 14; age range, 11.5-14.7 years) compared with controls (N = 15; age range, 11.2-15.5 years), with no impairment on simple word lists. Analysis of functional magnetic resonance imaging showed that adolescents with congenital hypothyroidism had both increased magnitude of hippocampal activation relative to controls and bilateral hippocampal activation when only the left was observed in controls. Furthermore, the increased activation in the congenital hypothyroidism group was correlated with the severity of the hypothyroidism experienced early in life.

- Willoughby et al., 2013 Analogously, in this study, fMRI revealed increased hippocampus activation with word pair recognition task in CH and children born to women with hypothyroxinemia during midgestation. These differences in functional activation were not seen with single word recognition, but were revealed when retention of word pair associations was probed. The latter is a task requiring engagement of the hippocampus.

A series of important findings suggest that the biochemical changes that happen after induction of LTP also occur during memory acquisition, showing temporality between the two KEs (reviewed in Lynch, 2004).

- Morris et al., 1986 This study found that blocking the NMDA receptor of the neuronal network with AP5 inhibits spatial learning in rats. Most importantly, in the same study they measured brain electrical activity and recorded that this agent also inhibits LTP, however, they have not proven that spatial learning and LTP inhibition are causally related.

Since then, a number of NMDA receptor antagonists have been studied towards their ability to induce impairment of learning and memory. It is worth mentioning that similar findings have been found in human subjects:

- Grunwald et al., 1999 By combining behavioural and electrophysiological data from patients with temporal lobe epilepsy exposed to ketamine, involvement of NMDA receptors in human memory processes was demonstrated.

 

The last KE preceding the AO (learning and memory deficits), i.e. "Decreased Neural Network Function", is also common to the AOP 13, entitled "Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities" (https://aopwiki.org/aops/13). In this AOP 13, data on lead (Pb) exposure as reference chemical are reported. While these studies do not refer to TH disruption, they provide empirical support for the same KER described in the present AOP.

Exposure to low levels of Pb2+ during early development has been implicated in long-lasting behavioural abnormalities and cognitive deficits in children (Needleman et al., 1975; Needleman and Gatsonis, 1990; Bellinger et al., 1991; 1992; Baghurst et al., 1992; Leviton et al., 1993; Needleman et al., 1996; Finkelstein et al., 1998; Lanphear et al., 2000; 2005; Canfield et al., 2003; Bellinger, 2004; Surkan et al., 2007; Jusko et al., 2008; Neal and Guilarte, 2010) and experimental animals (Brockel and Cory-Slechta, 1998; Murphy and Regan, 1999; Moreira et al., 2001). Multiple lines of evidence suggest that Pb2+ can impair hippocampus-mediated learning in animal models (reviewed in Toscano and Guilarte, 2005).

The majority of the studies addressing the effects of Pb2+ on hippocampal-associated spatial learning and memory processes have been carried out mainly in male rats (Cao et al., 2008, Gilbert et al., 2005); only a few studies have examined both sexes simultaneously (Jett et al., 1997, Xu et al., 2009).

- Jett et al., 1997 Female rats exposed to Pb2+ through gestation and lactation have shown more severe impairment of memory than male rats with similar Pb2+ exposures.

- De Souza Lisboa et al., 2005 This study reported that exposure to Pb2+ during both pregnancy and lactation caused depressive-like behaviour (detected in the forced swimming test) in female but not male rats.

- Anderson et al., 2012 This study investigated the neurobehavioral outcomes in Pb2+-exposed rats (250, 750 and 1500 ppm Pb2+ acetate in food) during gestation and through weaning and demonstrated that these outcomes are very much influenced by sex and rearing environment. In females, Pb2+ exposure lessened some of the benefits of enriched environment on learning, whereas, in males, enrichment does help to overcome detrimental effects of Pb2+ on learning. Regarding reference memory, environmental enrichment has not been beneficial in females when exposure to Pb2+ occurs, in contrast to males.

- Jaako-Movits et al., 2005 Wistar rat pups were exposed to 0.2% Pb2+ via their dams' drinking water from PND 1 to PND 21 and directly via drinking water from weaning until PND 30. At PND 60 and 80, the neurobehavioural assessment has revealed that developmental Pb2+ exposure induces persistent increase in the level of anxiety and inhibition of contextual fear conditioning. The same behavioural syndrome in rats has been described in Salinas and Huff, 2002.

- Finkelstein et al., 1998 These observations are in agreement with observations on humans, as children exposed to low levels of Pb2+ displayed attention deficit, increased emotional reactivity and impaired memory and learning.

- Kumar and Desiraju, 1992 In Wistar rats fed with lead acetate (400 µg/g body weight/day) from PND 2 until PND 60, EEG findings showed statistically significant reduction in the delta, theta, alpha and beta band EEG spectral power in motor cortex and hippocampus, but not in delta and beta bands power of motor cortex in wakeful state. After 40 days of recovery, animals were assessed for their neurobehaviour, and revealed that Pb2+ treated animals showed more time and sessions in attaining criterion of learning than controls.

Further data obtained using animal behavioral techniques demonstrate that NMDA mediated synaptic transmission is decreased by Pb2+ exposure (Cory-Slechta, 1995; Cohn and Cory-Slechta, 1993 and 1994).

- Xiao et al., 2014 Rat pups from parents exposed to 2 mM PbCl2 three weeks before mating until their weaning (pre-weaning Pb2+) and weaned pups exposed to 2 mM PbCl2 for nine weeks (post-weaning Pb2+) were assessed for their spatial learning and memory by MWM on PND 85-90. The study revealed that both rat pups in pre-weaning Pb2+ and post-weaning Pb2+ groups performed significantly worse than those in the control group. The number of synapses in pre-weaning Pb2+ group increased significantly, but it was still less than that of control group. The number of synapses in post-weaning Pb2+ group was also less than that of control group, although the number of synapses had no differences between post-weaning Pb2+ and control groups before MWM. In both pre-weaning Pb2+ and post-weaning Pb2+ groups, synaptic structural parameters such as thickness of postsynaptic density (PSD), length of synaptic active zone and synaptic curvature increased, whereas width of synaptic cleft decreased compared to controls.

 

 

One of the most difficult issues for neuroscientists is to link neuronal network function to cognition, including learning and memory. It is still unclear what modifications of neuronal circuits need to occur in order to alter motor behaviour as it is recorded in a learning and memory test (Mayford et al., 2012), meaning that there is no clear understanding about how these two KEs are connected.

The direct relationship of alterations in neural network function and specific cognitive deficits is difficult to ascertain given the many forms that learning and memory can take and the complexity of synaptic interactions in even the simplest brain circuit. Linking of neurophysiological assessments to learning and memory processes have, by necessity, been made across simple monosynaptic connections and largely focused on the hippocampus. Alterations in synaptic function have been found in the absence of behavioral impairments. This may result from measuring only one component in the complex brain circuitry that underlies 'cognition', behavioral tests that are not sufficiently sensitive for the detection of subtle cognitive impairments, and behavioral plasticity whereby tasks are solved by the animal via different strategies developed as a consequence of developmental insult.

Finally, in order to provide empirical support for this KER, data on the effects of lead (Pb) exposure are reported. However, Pb exposure is not always associated with learning and memory impairment in children. In this regard, Koller's review has commented that in some occasions, low-level Pb dose and cognitive deficits of the subjects are negatively correlated, and this may be due to the high influence of social and parenting factors in cognitive ability, like learning and memory (Koller et al., 2004).

Biological Plausibility

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Long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy (not always and not always high frequency stimulation leads to LTP), and its discovery suggested that changes in synaptic strength could provide the substrate for learning and memory (reviewed in Lynch, 2004). Moreover, LTP is intimately related to the theta rhythm, an oscillation long associated with learning. Learning-induced enhancement in neuronal excitability, a measurement of neural network function, has also been shown in hippocampal neurons following classical conditioning in several experimental approaches (reviewed in Saar and Barkai, 2003).

On the other hand, memory requires the increase in magnitude of EPSCs to be developed quickly and to be persistent for few weeks at least without disturbing already potentiated contacts. Once again, a substantial body of evidence has demonstrated that tight connection between LTP and diverse instances of memory exist (reviewed in Lynch, 2004).

A review on Morris water maze (MWM) as a tool to investigate spatial learning and memory in laboratory rats also pointed out that the disconnection between neuronal networks rather than the brain damage of certain regions is responsible for the impairment of MWM performance. Functional integrated neural networks that involve the coordination action of different brain regions are consequently important for spatial learning and MWM performance (D'Hooge and De Deyn, 2001).

Moreover, it is well accepted that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function. There are a number of studies that have linked exposure to TPO inhibitors (e.g., PTU, MMI), as well as iodine deficient diets, to changes in serum TH levels, which result in alterations in both synaptic function and cognitive behaviors (Akaike et al., 1991; Vara et al., 2002; Gilbert and Sui, 2006; Axelstad et al., 2008; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016), described in the indirect KER "Decrease of TH synthesis leads to learning and memory deficits".

Empirical Support for Linkage

?

Developmental hypothyroidism reduces the functional integrity in brain regions critical for learning and memory. Neurophysiological indices of synaptic transmission of excitatory and inhibitory circuitry are impaired in the hippocampus of hypothyroid animals. Both hippocampal regions (area CA1 and dentate gyrus) exhibit alterations in excitatory and inhibitory synaptic transmission following reductions in serum TH in the pre and early postnatal period (Vara et al., 2002; Sui and Gilbert, 2003; Sui et al., 2005; Gilbert and Sui, 2006; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). These alterations persist into adulthood despite a recovery to euthyroid conditions in blood. The latter observation indicates that these alterations represent permanent changes in brain function caused by transient hormones insufficiencies induced during critical window of development.  

Because the adult hippocampus is involved in learning and memory, it is a brain region of remarkable plasticity. Use-dependent synaptic plasticity is critical during brain development for synaptogenesis and fine tuning of synaptic connectivity. In the adult brain, similar plasticity mechanisms underlie use-dependency that underlies learning and memory, as exhibited in LTP model of synaptic memory. Hypothyroidism during development reduces the capacity for synaptic plasticity in juvenile and adult offspring (Vara et al., 2002; Sui and Gilbert, 2003; Dong et al., 2005; Sui et al., 2005; Gilbert and Sui, 2006; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). Decrease of neuronal network function and plasticity are observed coincident with deficits in learning tasks that require the hippocampus.

- Wang et al., 2012: This study showed that maternal subclinical hypothyroidism impairs spatial learning in the offspring, as well as the efficacy and optimal time of T4 treatment in pregnancy. Female adult Wistar rats were randomly divided into six groups: control, hypothyroid (H), subclinical hypothyroid (SCH) and SCH treated with T4, starting from GD10, GD13 and GD17, respectively, to restore normal TH levels. Results indicate that progenies of SCH and H groups demonstrated significantly longer mean latency in the water maze test (on the 2nd training day, latency was ~83% higher in H group, and ~50% higher in SCH), and a lower amplification percentage of the amplitude (~15% lower in H group, and 12% lower in SCH), and slope of the field excitatory postsynaptic potential (fEPSP) recording (~20% lower in H group, and 17% lower in SCH), compared to control group. T4 treatment at GD10 and GD13 significantly shortened mean latency and increased the amplification percentage of the amplitude and slope of the fEPSPs of the progeny of rats with subclinical hypothyroidism. However, T4 treatment at GD17 showed only minimal effects on spatial learning in the offspring. Altogether these data indicate direct correlation between decrease of neural network function and learning and memory deficits.

- Liu et al., 2010 This study assessed the effects of hypothyroidism in 60 female rats who were divided into three groups: (i) maternal subclinical hypothyroidism (total thyroidectomy with T4 infusion), (ii) maternal hypothyroidism (total thyroidectomy without T4 infusion), and (iii) control (sham operated). The Morris water maze tests revealed that pups from the subclinical hypothyroidism group showed long-term memory deficits, and a trend toward short-term memory deficits.

- Gilbert and Sui, 2006 Administration of 3 or 10 ppm PTU to pregnant and lactating dams via the drinking water from GD6 until PND30 caused a 47% and 65% reduction in serum T4, in the dams of the low and high-dose groups, respectively. Baseline synaptic transmission was impaired in PTU-exposed animals: mean EPSP slope (by ~60% with 10 ppm PTU) and population spike amplitudes (by ~70% with 10 ppm PTU) in the dentate gyrus were reduced in a dose-dependent manner in adult offspring of PTU-treated dams. High-dose animals (10 ppm) demonstrated very little evidence of learning despite 16 consecutive days of training (~5-fold higher mean latency to find the hidden platform, used as an index of learning).

- Gilbert et al., 2016 Exposure to PTU during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. Developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes in neonate hippocampus and was accompanied by deficits in hippocampal-based learning (e.g., mean latency to find a hidden platform, at 2nd trial resulted ~60% higher in rats treated with 10 ppm PTU).

- Gilbert, 2011 Trace fear conditioning deficits to context and to cue reported in animals treated with PTU and who also displayed synaptic transmission and LTP deficits in hippocampus. Baseline synaptic transmission was impaired in PTU-exposed animals (by ~50% in animal treated with 3 ppm PTU). EPSP slope amplitudes in the dentate gyrus were reduced in a dose-dependent manner in adult offspring of PTU-treated dams.

 

BPA, an environmental toxicant known to inhibit NIS-mediated iodide uptake (Wu Y et al., 2016) has been found to cause learning and memory deficits in rodents as described below:

- Jang et al., 2012 In this study, pregnant female C57BL/6 mice (F0) were exposed to BPA (0.1-10 mg/kg) from gestation day 6 to 17, and female offspring (F2) from F1 generation mice were analysed. Exposure of F0 mice to BPA (10 mg/kg) decreased hippocampal neurogenesis (~ 30% decrease of hippocampal BrdU+ cells vs control) in F2 female mice. High-dose BPA (10 mg/kg) caused neurocognitive deficit (i.e., reduced memory retention) as shown by passive avoidance testing (~ 33% decrease vs control) in F2 mice. Furthermore, 10 mg/kg BPA decreased the hippocampal levels of BDNF (~ 35% lower vs control) in F2 mice. These results suggest that BPA exposure (NIS inhibitor) in pregnant mothers could decrease hippocampal neurogenesis (decreased number of neurons) and cognitive function in future generations.

 

In humans, the data linking these two specific KE are much more limited, but certainly clear reductions in IQ, with specific impairments in hippocampus-mediated functions have been observed.

- Wheeler et al., 2015 This study assessed hippocampal functioning in adolescents with congenital hypothyroidism (CH), using functional magnetic resonance imaging (fMRI). 14 adolescents with CH and 14 typically developing controls (TDC) were studied. Hippocampal activation was greater for pairs than items in both groups, but this difference was only significant in TDC. When the groups were directly compared, the right anterior hippocampus was the primary region in which the TDC and CH groups differed for this pair memory effect. Results signify that adolescents with CH show abnormal hippocampal functioning during verbal memory processing, in order to compensate for the effects induced by TH deficit in the brain.

- Wheeler et al., 2012 In this study hippocampal neuronal network function was measured based on synaptic performance using fMRI and was altered while subjects engaged in a memory task. Data showed paired word recognition deficits in adolescents with congenital hypothyroidism (N = 14; age range, 11.5-14.7 years) compared with controls (N = 15; age range, 11.2-15.5 years), with no impairment on simple word lists. Analysis of functional magnetic resonance imaging showed that adolescents with congenital hypothyroidism had both increased magnitude of hippocampal activation relative to controls and bilateral hippocampal activation when only the left was observed in controls. Furthermore, the increased activation in the congenital hypothyroidism group was correlated with the severity of the hypothyroidism experienced early in life.

- Willoughby et al., 2013 Analogously, in this study, fMRI revealed increased hippocampus activation with word pair recognition task in CH and children born to women with hypothyroxinemia during midgestation. These differences in functional activation were not seen with single word recognition, but were revealed when retention of word pair associations was probed. The latter is a task requiring engagement of the hippocampus.

A series of important findings suggest that the biochemical changes that happen after induction of LTP also occur during memory acquisition, showing temporality between the two KEs (reviewed in Lynch, 2004).

- Morris et al., 1986 This study found that blocking the NMDA receptor of the neuronal network with AP5 inhibits spatial learning in rats. Most importantly, in the same study they measured brain electrical activity and recorded that this agent also inhibits LTP, however, they have not proven that spatial learning and LTP inhibition are causally related.

Since then a number of NMDA receptor antagonists have been studied towards their ability to induce impairment of learning and memory. It is worth mentioning that similar findings have been found in human subjects:

- Grunwald et al., 1999 By combining behavioural and electrophysiological data from patients with temporal lobe epilepsy exposed to ketamine, involvement of NMDA receptors in human memory processes was demonstrated.

 

Pb2+: Exposure to low levels of Pb2+, during early development, has been implicated in long-lasting behavioural abnormalities and cognitive deficits in children (Needleman et al., 1975; Needleman and Gatsonis, 1990; Bellinger et al., 1991; 1992; Baghurst et al., 1992; Leviton et al., 1993; Needleman et al., 1996; Finkelstein et al., 1998; Lanphear et al., 2000; 2005; Canfield et al., 2003; Bellinger 2004; Lanphear et al., 2005; Surkan et al., 2007; Jusko et al., 2008; Neal and Guilarte, 2010) and experimental animals (Brockel and Cory-Slechta, 1998; Murphy and Regan, 1999; Moreira et al., 2001). Multiple lines of evidence suggest that Pb2+ can impair hippocampus-mediated learning in animal models (reviewed in Toscano and Guilarte, 2005).

The majority of the studies addressing the effects of Pb2+ on hippocampal-associated spatial learning and memory processes have been carried out mainly in male rats (Cao et al., 2008, Gilbert et al., 2005); only a few studies have examined both sexes simultaneously (Jett et al., 1997, Xu et al., 2009). Female rats exposed to Pb2+ through gestation and lactation have shown more severe impairment of memory than male rats with similar Pb2+ exposures (Jett et al., 1997). De Souza Lisboa et al. (2005) have reported that exposure to Pb2+ during both pregnancy and lactation causes depressive-like behaviour (detected in the forced swimming test) in female but not male rats. A more recent study has investigated the neurobehavioral outcomes in Pb2+-exposed rats (250, 750 and 1500 ppm Pb2+ acetate in food) during gestation and through weaning and demonstrated that these outcomes are very much influenced by sex and rearing environment (Anderson et al., 2012). In females, Pb2+ exposure lessens some of the benefits of enriched environment on learning, whereas, in males, enrichment does help to overcome detrimental effects of Pb2+ on learning. Regarding reference memory, environmental enrichment has not been beneficial in females when exposure to Pb2+ occurs, in contrast to males (Anderson et al., 2012).

Wistar rat pups were exposed to 0.2% Pb2+ via their dams' drinking water from PND 1 to PND 21 and directly via drinking water from weaning until PND 30 (Jaako-Movits et al., 2005). At PND 60 and 80, the neurobehavioural assessment has revealed that developmental Pb2+ exposure induces persistent increase in the level of anxiety and inhibition of contextual fear conditioning (Jaako-Movits et al., 2005). The same behavioural syndrome in rats has been described in Salinas and Huff, 2002 and is in agreement with observations on humans as children exposed to low levels of Pb2+ display attention deficit, increased emotional reactivity and impaired memory and learning (Finkelstein et al., 1998).

In experiments carried out in Wistar rats that were fed with lead acetate (400 micrograms lead/g body weight/day) from PND 2 until PND 60, EEG findings show statistically significant reduction in the delta, theta, alpha and beta band EEG spectral power in motor cortex and hippocampus but not in delta and beta bands power of motor cortex in wakeful state (Kumar and Desiraju, 1992). After 40 days of recovery, animals have been assessed for their neurobehaviour and revealed that Pb2+ treated animals show more time and sessions in attaining criterion of learning than controls (Kumar and Desiraju, 1992). Further data obtained using animal behavioral techniques demonstrate that NMDA mediated synaptic transmission is decreased by Pb2+ exposure (Cory-Slechta, 1995; Cohn and Cory-Slechta, 1993; 1994).

Rat pups from parents exposed to 2 mM PbCl2 3 weeks before mating until their weaning (pre-weaning Pb2+) and weaned pups exposed to 2 mM PbCl2 for 9 weeks (post-weaning Pb2+) were assessed for their spatial learning and memory by MWM on PND 85-90 (Xiao et al., 2014). The study revealed that both rat pups in pre-weaning Pb2+ and post-weaning Pb2+ groups performed significantly worse than those in control group (Xiao et al., 2014).

The number of synapses in pre-weaning Pb2+ group increased significantly, but it was still less than that of Control group (p<0.05); the number of synapses in post-weaning Pb2+ group was also less than that of control group (p<0.05), although the number of synapses has no differences between post-weaning Pb2+ and control groups before MWM. In both pre-weaning Pb2+ and post-weaning Pb2+ groups, synaptic structural parameters such as thickness of postsynaptic density (PSD), length of synaptic active zone and synaptic curvature increased whereas width of synaptic cleft decreased compared to controls (Xiao et al., 2014).

Uncertainties or Inconsistencies

?

One of the most difficult issues for neuroscientists is to link neuronal network function to cognition, including learning and memory. It is still unclear what modifications of neuronal circuits need to happen in order to alter motor behaviour as it is recorded in a learning and memory test (Mayford et al., 2012), meaning that there is no clear understanding about the how these two KEs are connected.

Several epidemiological studies where Pb2+ exposure levels have been studied in relation to neurobehavioural alterations in children have been reviewed in Koller et al. 2004. This review has concluded that in some occasions there is negative correlation between Pb2+ dose and cognitive deficits of the subjects due to high influence of social and parenting factors in cognitive ability like learning and memory (Koller et al. 2004), meaning that not always Pb2+ exposure is positively associated with learning and memory impairment in children.

The direct relationship of alterations in neural network function and specific cognitive deficits is difficult to ascertain given the many forms that learning and memory can take and the complexity of synaptic interactions in even the simplest brain circuit. Linking of neurophysiological assessments to learning and memory processes have, by necessity, been made across simple monosynaptic connections and largely focused on the hippocampus. Alterations in synaptic function have been found in the absence of behavioral impairments. This may result from measuring only one component in the complex brain circuitry that underlies 'cognition', behavioral tests that are not sufficiently sensitive for the detection of subtle cognitive impairments, and behavioral plasticity whereby tasks are solved by the animal via different strategies developed as a consequence of developmental insult.

Quantitative Understanding of the Linkage

?


There is not enough quantitative information how much change decrease of neuronal network functions leads to learning and memory deficits. However, qualitatively is well documented that decrease of LTP is directly linked to learning and memory deficits.

There is very limited information on the degree of quantitative change in neural network function required to alter cognitive behaviors. This is a result of the diversity of methods for measuring both neuronal network function and learning and memory deficits, which hamper cross-study analyses. This highlights the need to develop empirical data based models of this KER. It is well known that the altered balance between excitatory and inhibitory synapses affects learning and memory, although no quantitative data are available.

Evidence Supporting Taxonomic Applicability

?


Synaptic transmission and plasticity are achieved via mechanisms common across taxonomies. LTP has been recorded in aplysia, lizards, turtles, birds, mice, guinea pigs, rabbits and rats. Deficiencies in hippocampally based learning and memory following developmental hypothyroidism have been documented mainly in rodents and humans.

References

?


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