www.sciencemag.org/cgi/content/full/340/6130/363/DC1
Supplementary Materials for
Bat and Rat Neurons Differ in Theta-Frequency Resonance Despite
Similar Coding of Space
James G. Heys,* Katrina M. MacLeod, Cynthia F. Moss, Michael E. Hasselmo*
*Corresponding author. E-mail: [email protected] (M.E.H.); [email protected] (J.G.H.)
Published 19 April 2013, Science 340, 363 (2013)
DOI: 10.1126/science.1233831
This PDF file includes:
Materials and Methods
Supplementary Text
Figs. S1 to S3
References
Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
Supporting Online Material for:
Bat and Rat Neurons Differ in Theta Frequency Resonance
Despite Similar Coding of Space
James G. Heys1*, Katrina M. MacLeod2, Cynthia F. Moss3,
and Michael E. Hasselmo4*
1. Graduate Program for Neuroscience, Center for Memory and Brain, Boston
University, 2 Cummington St., Boston, Massachusetts, 02215, U.S.A. 2. Department of
Biology, University of Maryland, College Park, MD 20742, 3. Department of
Psychology, University of Maryland, College Park, MD 20742, U.S.A. 4. Department of
Psychology, Center for Memory and Brain, Boston University, 2 Cummington St.,
Boston, Massachusetts, 02215, U.S.A.
* To whom correspondence should be addressed: [email protected] and
[email protected]
This file includes:
Materials and Methods
Supplementary Text
Figure Legends S1-S3
Supplemental References
Figs. S1-S3
Page 1
Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
Methods
Slice preparation. Recordings were made from 26 neurons in 12 adult male and female
Big Brown Bats (Eptesicus fuscu) and 14 neurons in 6 male and female Long-Evans rats.
In addition, recordings were made from 6 cells from in two Egyptian Fruit Bats
(Rousettus aegyptiacus) which are included in the supplemental material. The Big Brown
Bat and the Egyptian Fruit Bat are the species of bat used in (17) and (5), respectively.
All procedures were in accordance with the Institutional Animal Care and Use
Committee of UMPC. Animals were deeply anesthetized using isofluorane and rapidly
decapitated. Immediately after decapitation the brain was removed from the skull and
placed in oxygenated 4oC artificial cerebral spinal fluid (ACSF) with the following
concentrations (in mM): NaCl 130, KCl 3, MgCl2 2, NaHCO3 26, CaCl2 2, NaH2PO4
1.25, HEPES 3, dextrose 12. The osmolarity of the ACSF was adjusted to be within a
range of 305-325 mOsm. On six recording sessions in the bat brain (Eptesicus fuscus), a
modified incubation solution was used which replaced NaCl with 130 mM NMDG (45).
Slices were kept in this solution for 12 minutes immediately after sectioning and
subsequently transferred to normal recording solution for the reminder of the incubation
period. Three bat neurons recorded using this solution did not show any differences in
physiology, including resting membrane potential, spike threshold, sag ratio or resonance
frequency, from bat neurons held in the normal incubation solution and were included
into the population of bat neurons. After extraction the brain was blocked and 300μm
horizontal sections were cut using a vibratome. After sectioning the brain slices were
incubated in a holding chamber for 30 minutes at 31oC and subsequently incubated at
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Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
Page 3
room temperature for 30 minutes before recording. Recordings were made from both rats
and bats using the same solutions and experimental recording equipment. No synaptic
blockers were used in the recordings.
Electrophysiological recordings. Slices were placed in a 20 series holding chamber and
bathed in 37oC oxygenated ACSF. A pipette puller was used to manufacture 4-6 MΩ
borosilicate glass patch clamp pipettes and filled with internal recording solution with the
following concentrations (in mM): 110 K-gluconate, 20mM KCl, 1 EGTA, 2 MgCl2, 10
HEPES, 2 Na2ATP, 0.3 Na2GTP, 10 phosphocreatine and 0.1% biocytin. Neurons were
visually identified using a differential interference contrast microscope and confirmed to
be layer II cells by the proximity to the superficial edge of the horizontal slice.
In the
recordings from rat slices, the layer II neurons were further classified as stellate cells due
to their morphology and characteristic electrophysiological profile (21, 22, 43). In the
bat, the recordings were made from a wide range of locations along the medial-lateral and
dorsal-ventral axis of the brain. Whole cell patch clamp recordings were obtained using
brief pulses of inward pressure after giga-ohm seals were formed. Pipette capacitance
and bridge balance compensation was made using a Multiclamp 700B amplifier. The
data were low pass filtered at 10 kHz, digitized using a National Instruments board and
sampled at a rate of 30 KHz using custom written IGOR Pro acquisition software. All
recordings were not corrected for the liquid junction potential, which was measured to be
6mV (44). The morphology of neurons were identified using biocytin staining and
imaged according to procedures outlined in (7, 44). In the bat brain successive horizontal
6 slices were taken from each hemisphere along the dorsal-ventral axis. Approximately
1.2mm was removed from the dorsal surface of the brain before the first slices was cut, at
Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
Page 4
which point the hippocampus could be visualized and slices were categorized as dorsal
(1.2mm-2.1mm from the dorsal surface) or ventral (2.1-3.0mm from the dorsal surface).
Similarly, in the rat brain, 3.6mm was removed from the dorsal surface and slices were
categorized as dorsal (3.6-4.8mm from the dorsal surface) and ventral (4.8mm-6.0mm
from the dorsal surface).
Data Analysis. All data were analyzed using MATLAB.
Kruskal-Wallis one non-
parametric one-way ANOVA was used in all statistical comparisons to avoid
assumptions of normality. Using a 3 second pulse, hyperpolarzing current steps were
injected from a membrane potential of -60mV to generate a sag response in both bat and
rat neurons. The sag ratio was computed as the difference between the initial voltage and
the initial peak voltage after the hyperpolarzing current step, divided by the difference
between the initial peak voltage after the hyperpolarizing current step and the steady state
voltage after the hyperpolarizing current step.
The sag time constant (τsag) was
determined by fitting the sag with an exponential function of the form:
where
is membrane potential, A1 and A2 are constants. To generate a frequency
dependent response to the injected current the MATLAB chirp function was used to
generate current stimuli that varied linearly in frequency from 0 to 20 Hz or 0 to 10 Hz
over 20 seconds. The impedance profile of the neural response was calculated according
to pervious techniques (40, 41). In short, the impedance profile was computed as the
Fast-Fourier transform of the voltage response divided by the Fast-Fourier transform of
the injected current. The impedance profile was characterized by fitting the data with an
Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
nth (n
{4,5,6}) order polynomial that minimized the adjusted-R2. Using this function,
the resonance frequency (fr) was computed as input frequency that gave the maximum of
the fit to the impedance profile. Similarly the resonance strength was computed using the
fit as the ratio of amplitude of the impedance profile at the resonance frequency divided
by the amplitude of the impedance profile at the Y-intercept.
Biophysical Model. Using the NEURON biophysical simulation software, standard
morphologies for a bat model cell and a rat model cell were generated by including
average morphological data from 4 bat neurons for the bat model and 4 rat neurons for
the rat model that were completely filled. The mean number of processes, mean length of
processes and mean somatic area were measured from the fills of the rat and bat neurons
and these values were included into morphological specification of the two different
models.
The current balance equation was modeled using the Hodgkin-Huxley formalism in an
equivalent circuit representation of membrane potential dynamics as follows:
Cm
_
_
_
dV
= (n* g H ( fast ) + k* g H ( slow ) )* (V m – E H ) + g leak *( V m – Eleak ) + I a p p
dt
where V m (mV) is the membrane potential, Cm (µF/cm2) is the membrane capacitance,
Eleak (mV) is the reversal potential for the passive leak conductance. For different
_
components of membrane conductance,
gx
(mS/cm2) indicates the maximum
conductance density and I a p p represents injected current. The kinetics of the fast and
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Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
Page 6
slow components of the h current are described by the gating variables n and k,
respectively. The gating variables were modeled using the following form:
dx ( xinf  x)

dt
x
where xin f is the steady state activation function for the h current, which is modeled
according to (41), and  x is the gating variable time constant. The parameterization for
_
g leak and Cm for model cell of each species were fit using depolarizing current steps to
induce voltage responses from an initial membrane potential of approximately -60mV to
a steady state membrane potential of approximately -55mV, which was chosen to
minimize the influence of h current on the membrane physiology and ensure the cell was
below spiking threshold. The h current reversal potential was set to -30mV according to
(26) and the reversal potential for the leak conductance was set for the bat and rat model
neurons to match the average resting potential measured in the experimental recordings
(see below). The h current steady state activation was set according to (41).
The h
current density and time constant were modeled by fitting these parameters to match the
sag response that occurred with steps from an initial membrane potential of
approximately -60mV to a steady state membrane potential of approximately -80mV.
Supplemental Material
Anatomy and Morphology
Although neurons in the bat showed similar patterns of arborization, compared to stellate
cells in rat, the length of dendrites and soma size differed significantly in 4 bat neurons
and 4 rat SCs that were completely filled (mean length of dendritic branches: Bat =
Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
83.23±5.82µm (n=62), Rat = 123.52±6.17µm (n=97) (p<0.01); mean perimeter of soma:
Bat = 50.48±2.92µm (n=4), Rat = 79.28±7.54µm (n=4) (p<0.05). In addition there was a
trend towards increased number of processes in the rat neurons, however this measure
was not statistically significant (mean number of processes: Bat = 15.50±1.94 (n=4), Rat
= 24.50±6.15 (n=4) (p=0.1913). As this is the first known study to report whole cell
patch clamp measurements in slices of the bat brain, there are no previous data to control
for the possibility of recording from several distinct physiological cell types. To ensure
that our recordings in the bat slices included a population of neurons located in mEC,
recording locations were chosen in order to sample a wide range of medial to lateral
positions along the parahippocampal area. Furthermore, the neurons were confirmed to
be located in layer II based upon their position relative to the superficial border of the
horizontal slice, as layer II neurons are tightly packed in a dense cell layer as compared to
layer III (20, 42) and are the first to appear when moving to deeper positions from the
edge of the slice (Fig. S1). As the resonance frequency has been shown to vary as a
function of the distance from the dorsal border of medial entorhinal cortex (7) we made
measurements of the resonance frequency according to the neuron’s anatomical position
along the dorsal-ventral axis. The resonance frequency in the bat, measured at -80mV,
did not vary significantly as a function of distance from the dorsal surface of the brain as
the 95% confidence bounds on the slope coefficient were (-1.049, 0.6714) (Fig. S3A,
top). Similarly, at -80mV there was no significant relationship between the position of
recording location along the dorsal-ventral axis and the resonance strength as the 95%
confidence bounds of the slope coefficient were (-0.1206, 0.03533) (Fig. S3A, bottom).
To control for the possibility that resonance frequency may also change as a function of
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Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
medial-lateral position we recorded the distance from labeled cell to the medial border of
the horizontal slice. Our data indicate there is no statistically significant relationship
between resonance frequency and medial-lateral position as the 95% confidence bounds
for the slope coefficient were (-0.0002253, 0.0008357) (Fig S3B, top). The data also
indicate that there is no significant relationship between recording location along the
medial-lateral axis and the resonance strength (Fig. S3B, bottom). The 95% confidence
bounds of the slope coefficient are (-6.222e-05, 2.973e-05).
Physiology
Neurons in the bat have both higher input resistance (Bat = 159.88±10.00 MΩ (n=26
cells), Rat = 72.28±8.42 MΩ (n=14 cells) (p<0.01)) and more hyperpolarized resting
membrane potential (Bat = -64.31±1.21mV (n=26 cells), Rat = -60.71mV (n=14 cells)
(p<0.05)). In response to the chirp stimulus ranging from 0 to 20 Hz, neurons in the bat
revealed a low-pass response, with resonance frequency below the theta band. Bat
neurons also exhibited lower resonance strength. To ensure that resonance strength and
resonance frequency was not occurring more strongly at lower frequencies, we used chirp
stimuli that ranged from 0 to 10 Hz over 20 seconds to allow for more sampling of the
frequency response at lower frequency bands (Fig. S2A). The results using both chirp
stimuli are consistent and clearly demonstrate that bat neurons do not have theta band
membrane potential resonance (bat resonance frequency with chirp 0 to 10Hz =
1.62±0.16 Hz (n=12); bat resonance frequency with chirp 0 to 20Hz = 1.72±0.22 Hz
(n=12) (p=0.86)). Similarly, resonance frequency at -80mV did not change using this
lower frequency chirp stimuli (bat resonance frequency with chirp 0 to 10Hz = 1.53±0.14
Hz (n=12); bat resonance frequency with chirp 0 to 20Hz = 1.96±0.30 Hz (n=12)
Page 8
Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
(p=0.817)). In addition, the resonance strength at -70mV, across the two populations of
bat neurons, did not change using the lower frequency chirp stimuli (bat resonance
strength with chirp 0 to 10 Hz = 1.11±0.02 (n=12); bat resonance strength with chirp 0 to
20 Hz=1.10±0.03 (n=12) (p=0.602)). The resonance strength at -80mV, across the two
populations of bat neurons, did not change using the lower frequency chirp stimuli (bat
resonance strength with chirp 0 to 10 Hz = 1.07±0.02 (n=12); bat resonance strength with
chirp 0 to 20 Hz=1.05±0.02 (n=12) (p=0.24)). In addition the raw impedance plots for
the normalized responses in Fig. 2 are shown in Fig S2B. While much of the data in the
bat brain presented in this study comes from the Big Brown Bat, as was used in (17), we
also sought to investigate the resonant properties of neurons in the Egyptian Fruit Bat,
which was used in (5). Similar to the Big Brown Bat, our results demonstrate that
neurons in medial entorhinal cortex of the Egyptian Fruit Bat also do not exhibit theta
band subthreshold membrane potential resonance (Fig. S2C and S2D).
Fig. S1. Recording locations and morphology of Big Brown Bat neurons. A. Recording
locations of 6 neurons are shown in 6 different slices from the bat brain. The recordings
locations demonstrate that neurons were recorded along an extensive region of the medial
to lateral axis of entorhinal cortex. B. Neurons recorded in the bat brain were stained
with biocytin and revealed to have a stellate-like appearance, which is similar in
morphology to the stellate cells in layer II of mEC in the rat. C. DIC image taken during
recording displays the position of the pipette in layer II of medial entorhinal cortex of the
bat.
Figure S2. Frequency selectivity of bat and rat neurons. A. Four example impedance
profiles are shown for the Big Brown Bat neurons at -70mV (top) and -80mV (bottom).
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Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
Impedance profiles using chirp stimuli ranging from 0 to 10 Hz over 20 seconds
demonstrate that the resonance frequency in bat neurons is not significantly different
from the group of bat neurons measured using a chirp stimulus ranging from 0 to 20H.
Polynomial fits to the data are shown in black. B. The impedance profile for the median
resonance frequency Big Brown bat and rat neurons shown in figure 1 are displayed here
without normalization. C. The resonance response of 3 example neurons in medial
entorhinal cortex of Egyptian Fruit Bat are shown using a chirp stimulus ranging from
0.001 Hz to 20 Hz, linearly over 20 seconds. D. The resonance frequency (left) was
significantly lower in in the Egyptian Fruit Bat compared to the rat and was not
statistically significantly different when compared across the Big Brown Bat and the
Egyptian Fruit Bat (Resonance Frequency measured at -70mV: Big Brown Bat = 1.67 ±
0.13 Hz (n = 24) vs Egyptian Fruit Bat = 1.60 ± 0.45 Hz (n=6) (p = 0.6828); Rat = 8.45 ±
1.19 Hz (n = 13) vs Egyptian Fruit Bat = 1.60 ± 0.45 Hz (n=6) (p<0.01). Similarly, the
resonance strength (right) was significantly lower in the Egyptian Fruit Bat compared to
the rat and not significantly different when compared across the two bat species
(Resonance strength measured at -70mV: Big Brown Bat = 1.10 ± 0.02 (n = 24) vs
Egyptian Fruit Bat = 1.0716 ± 0.04 (n=6) (p = 0.4837); Rat = 1.47 ± 0.07 (n = 13) (n =
13) vs Egyptian Fruit Bat = 1.0716 ± 0.04 (n=6) (p<0.01).
Figure S3. Resonance frequency and resonance strength in the Big Brown Bat measured
as a function of anatomical position. A. The resonance frequency (top) and resonance
strength (bottom), at -80mV, was measured as a function of the distance from the dorsal
surface of the brain. B. The resonance frequency (top) and resonance strength (bottom),
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Supporting Online Material – Heys, MacLeod, Moss, Hasselmo
at -80mV, was measured as function of the distance from the medial border of the
horizontal slice.
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Page 11
A
B
1mm
1mm
1mm
100µm
1mm
1mm
1mm
100µm
C
C
2 mV
Impedance (MΩ)
Impedance (MΩ)
A
Impedance (MΩ)
Supplementary Figure 2
2 sec
Frequency (Hz)
2 mV
Impedance (MΩ)
Impedance (MΩ)
Impedance (MΩ)
Frequency (Hz)
Frequency (Hz)
2 sec
Frequency (Hz)
Frequency (Hz)
Frequency (Hz)
B
2 sec
Impedance (MΩ)
rat
2 mV
bat
Cell APR1C2 at -70mV
Impedance (MΩ)
Impedance (MΩ)
Cell MAR28C2 at -70mV
Frequency (Hz)
Frequency (Hz)
Frequency (Hz)
D
Frequency (Hz)
rat
Frequency (Hz)
**
**
12
**
1.8
Resonance Strength
bat
Impedance (MΩ)
Impedance (MΩ)
Cell MAR28C2 at -80mV
**
Resonance Frequency (Hz)
Cell APR1C2 at -80mV
10
8
6
4
2
0
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Big Brown
Bat
1
Egyptian
Fruit Bat
Rat
Big Brown
Bat
1
Egyptian
Fruit Bat
Rat
B
Resonance Frequency (Hz)
Resonance Frequency (Hz)
Supplementary Figure 3
A 4
3
2
1
0
1
1.5
2
2.5
3
4
3
2
1
0
0
3.5
Depth from dorsal surface (mm)
2000
3000
Distance from medial border (μm)
1.3
Resonance Strength
1.3
Resonance Strength
1000
1.2
1.1
1.2
1.1
1
1
1
1.5
2
2.5
3
Depth from dorsal surface (mm)
0
1000
2000
3000
Distance from medial border (μm)
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